US20030042638A1 - Method of solubilizing and encapsulating itraconazole - Google Patents
Method of solubilizing and encapsulating itraconazole Download PDFInfo
- Publication number
- US20030042638A1 US20030042638A1 US10/222,640 US22264002A US2003042638A1 US 20030042638 A1 US20030042638 A1 US 20030042638A1 US 22264002 A US22264002 A US 22264002A US 2003042638 A1 US2003042638 A1 US 2003042638A1
- Authority
- US
- United States
- Prior art keywords
- phenyl
- acid
- lower alkyl
- solution
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 0 *C([Ar])(OCC)C([1*])([2*])N1C=CN=C1[3*].[4*]C Chemical compound *C([Ar])(OCC)C([1*])([2*])N1C=CN=C1[3*].[4*]C 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N CC(C)=O Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N [H]CCC(=O)O Chemical compound [H]CCC(=O)O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
Definitions
- the present invention relates to the preparation of solutions containing imidazole derivatives and to the use of those solutions in the preparation of microspheres.
- the imidazole derivative containing microspheres are effective in treating fungal infections, particularly in mammals.
- the microspheres facilitate the oral administration of relatively large amounts of the imidazole derivative, with increased bioavailability.
- the imidazole derivative family of compounds is particularly effective against a broad range of fungal infections such as those caused by Trichophyton rubrum, Tricophyton mentagrophytes, Epidermophyton flocesum, and Candida albicans, but these compounds are either partially water soluble or insoluble in water.
- the solubility of itraconazole in water is less than 0.00001 g/ml.
- imidazole derivatives are typically insoluble in water, they are difficult to administer orally. Consequently although imidazole derivatives are frequently prescribed for the treatment of fungal infections, they have been available only in topical preparations or in oral formulations with limited bioavailability.
- U.S. Pat. No. 3,717,655 discloses imidazole derivatives which have antifungal and antibacterial activity. These compounds are almost insoluble in aqueous solutions such as water and are very poorly soluble in polar solvents such as ethanol.
- R, R 1 , and R 2 are independently hydrogen or lower alkyl
- R 3 is hydrogen, methyl or ethyl
- R 4 is hydrogen or methyl
- Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;
- Ar 1 is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl;
- n 1 or 2;
- Imidazole derivative microspheres are also provided. These microspheres comprise:
- R, R 1 , and R 2 are independently hydrogen or lower alkyl
- R 3 is hydrogen, methyl or ethyl
- R 4 is hydrogen or methyl
- Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;
- Ar 1 is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl;
- n 1 or 2;
- Also contemplated by the present invention is a method for preparing these microspheres.
- the method comprises:
- R, R 1 , and R 2 are independently hydrogen or lower alkyl
- R 3 is hydrogen, methyl or ethyl
- R 4 is hydrogen or methyl
- Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;
- Ar 1 is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl;
- n 1 or 2;
- microsphere forming a carrier selected from the group consisting of
- the active agent and the carrier can be solubilized in separate solutions.
- the separate solutions can be nebulized together and the acid to water ratio then decreased as above.
- FIGS. 1 A- 1 H are scanning electron microspheres of itraconazole containing microspheres prepared according to the present invention.
- the active agents of the present invention are imidazole derivatives having the formula:
- R, R 1 and R 2 are independently hydrogen or lower alkyl
- R 3 is hydrogen, methyl or ethyl
- R 4 is hydrogen or methyl
- Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono (lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;
- Ar 1 is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl;
- n 1 or 2.
- a preferred imidazole derivative is itraconazole.
- Itraconazole is a synthetic triazole imidazole derivative 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers (Physicians Desk Reference 48th Ed., pg. 1097, 1994).
- solutions prepared in accordance with the present invention allow for the solubilization of imidazole derivatives at concentrations suitable for processing into orally administrable forms having acceptable bioavailability.
- imidazole derivatives are solubilized in volatile organic acid solvent(s).
- Preferred acid solvents for the imidazole derivatives are acetic acid and formic acid.
- the solvent itself is an aqueous solution of the acid.
- the volume:volume ratio of the acid to the total volume of the solvent is 3:7 or greater. It has been found that by using this solvent system up to a 50% solution of imidazole derivative can be prepared.
- Dissolution is achieved by simple mixing, with heating if necessary.
- the more concentrated the acid in the solvent the greater the amount of active agent that can be incorporated into the solution. If lower concentrations of acid are required for the end use of the solution, the active agent can first be dissolved in a more concentrated acid solution, and the resultant solution then slowly diluted further, preferably with water.
- the solution comprises from about 3 to about 40 percent by weight of solute and from about 60 to about 97 parts by weight of solvent based upon 100 parts by weight of solution.
- the solvent itself preferably comprises from about 30 to about 80 parts by volume of acid and from about 70 to about 20 parts by volume of water based upon 100 parts by volume of solvent. Most preferably, the solvent comprises from about 40 to about 50 parts by volume of acid and from about 60 to about 50 parts by volume of water based upon 100 parts by volume of solvent.
- Microspheres are useful in the delivery of active agents because they protect an active agent cargo until it is delivered to a target. Microspheres are particularly useful in the oral delivery of biologically active agents such as, for example, pharmaceutically active agents.
- Copending Application entitled “Method of Solubilizing and Encapsulating Itraconazole”, filed on [. . . ] discloses methods and apparatus for forming microspheres.
- Microspheres containing an active agent can be generally of the matrix form or the capsule form.
- the center of the sphere is hollow and the cargo or active agent is distributed throughout a carrier matrix.
- the carrier matrix forms a continuum in which the cargo is distributed.
- the encapsulated material or cargo can be either in solution or a solid, with the carrier forming a shell around the cargo.
- the methods of the present invention are cost-effective for preparing microspheres which contain imidazole derivatives, are simple to perform, and are amenable to industrial scale-up for commercial production.
- Carriers suitable for use in the present invention are microsphere forming carriers. These carriers include, without limitation, proteinoids; acylated amino acids, poly amino acids or salts thereof; sulfonated amino acids, poly amino acids or salts thereof; proteins or salts thereof, enteric coating materials; or any combination thereof.
- Amino acids are the basic materials used to prepare many of the carriers useful in the present invention.
- Amino acids include any carboxylic acid having at least one free amino group and include naturally occurring and synthetic amino acids.
- the preferred amino acids for use in the present invention are ⁇ -amino acids and, most preferably, are naturally occurring ⁇ -amino acids.
- Many amino acids and amino acid esters are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA); Sigma Chemical Co. (St. Louis, Mo., USA); and Fluka Chemical Corp. (Ronkonkoma, N.Y., USA).
- amino acids suitable for use in the present invention are generally of the formula
- R 5 is hydrogen, C 1 -C 4 alkyl, or C 2 -C 4 alkenyl
- R 6 is C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, phenyl, naphthyl, (C 1 -C 10 alkyl) phenyl, (C 2 -C 10 alkenyl) phenyl, (C 1 -C 10 alkyl) naphthyl, (C 2 -C 10 alkenyl) naphthyl, phenyl (C 1 -C 10 alkyl), phenyl (C 2 -C 10 alkenyl), naphthyl (C 1 -C 10 alkyl), or naphthyl (C 2 -C 10 alkenyl);
- R 6 being optionally substituted with C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, —OH, —SH, —CO 2 R 7 , C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, heterocycle having 3-10 ring atoms wherein the hetero atom is one or more of N, O, S, or any combination thereof, aryl, (C 1 -C 10 alk)aryl, ar(C 1 -C 10 alkyl) or any combination thereof;
- R 6 being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof;
- R 7 is hydrogen, C 1 -C 4 alkyl, or C 2 -C 4 alkenyl.
- amino acids or components of a peptide are alanine, arginine, asparagine, aspartic acid, citrulline cysteine, cystine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, hydroxyproline, ⁇ -carboxyglutamic acid, ⁇ -carboxyglutamic acid, phenylglycine, or O-phosphoserine.
- the most preferred amino acids are arginine, leucine, lysine, phenylalanine, tyrosine, tryptophan, valine, and phenylglycine.
- the preferred non-naturally occurring amino acids for use in the present invention are ⁇ -alanine, ⁇ -amino butyric acid, ⁇ -amino butyric acid, ⁇ -(aminophenyl) butyric acid, ⁇ -amino isobutyric acid, ⁇ -amino caproic acid, 7-amino heptanoic acid, ⁇ -aspartic acid, aminobenzoic acid, aminophenyl acetic acid, aminophenyl butyric acid, ⁇ -glutamic acid, cysteine (ACM), ⁇ -lysine, methionine sulfone, norleucine, norvaline, ornithine, d-ornithine, p-nitro-phenylalanine, hydroxy proline, 1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, and thioproline.
- ACM cysteine
- Poly amino acids are either peptides or two or more amino acids linked by a bond formed by other groups which can be linked, e.g., an ester or an anhydride linkage. Special mention is made of non-naturally occurring poly amino acids and particularly non-naturally occurring hetero-poly amino acids, i.e. of mixed amino acids.
- Peptides are two or more amino acids joined by a peptide bond. Peptides can vary in length from di-peptides with two amino acids to polypeptides with several hundred amino acids. See, Walker, Chambers Biological Dictionary, Cambridge, England: Chambers Cambridge, 1989, page 215. Special mention is made of non-naturally occurring peptides and particularly non-naturally occurring peptides of mixed amino acids. Special mention is also made of di-peptides tri-peptides, tetra-peptides, and penta-peptides, and particularly, the preferred peptides are di-peptides and tri-peptides. Peptides can be homo- or hetero- peptides and can include natural amino acids, synthetic amino acids, or any combination thereof.
- Proteinoids are artificial polymers of amino acids. Proteinoids preferably are prepared from mixtures of amino acids. Preferred proteinoids are condensation polymers, and most preferably, are thermal condensation polymers. These polymers may be directed or random polymers. Proteinoids can be linear, branched, or cyclical, and certain proteinoids can be units of other linear, branched, or cyclical proteinoids.
- Diketopiperazines are six member ring compounds.
- the ring includes two nitrogen atoms and is substituted at two carbons with two oxygen atoms.
- the carbonyl groups are at the 2 and 5 ring positions. These rings can be optionally, and most often are, further substituted.
- Diketopiperazine ring systems may be generated during thermal polymerization or condensation of amino acids or amino acid derivatives. (Gyore, J; Ecet M. Proceedings Fourth ICTA ( Thermal Analysis ), 1974, 2, 387-394 (1974)). These six membered ring systems were presumably generated by intra-molecular cyclization of the dimer prior to further chain growth or directly from a linear peptide (Reddy, A. V., Int. J. Peptide Protein Res., 40, 472-476 (1992); Mazurov, A. A. et al., Int. J. Peptide Protein Res., 42, 14-19 (1993)).
- Diketopiperazines can also be formed by cyclodimerization of amino acid ester derivatives as described by Katchalski et al., J. Amer. Chem. Soc., 68, 879-880 (1946), by cyclization of dipeptide ester derivatives, or by thermal dehydration of amino acid derivatives and high boiling solvents as described by Kopple et al., J. Org. Chem., 33 (2), 862-864 (1968).
- Diketopiperazines typically are formed from ⁇ -amino acids.
- the ⁇ -amino acids of which the diketopiperazines are derived are glutamic acid, aspartic acid, tyrosine, phenylalanine, and optical isomers of any of the foregoing.
- Modified amino acids, poly amino acids, or peptides are either acylated or sulfonated and include amino acid amides and sulfonamides.
- Ar 2 is a substituted or unsubstituted phenyl or naphthyl
- R 8 has the formula
- R 9 is C 1 to C 24 alkyl, C 1 to C 24 alkenyl, phenyl, naphthyl, (C 1 to C 10 alkyl) phenyl, (C 1 to C 10 alkenyl) phenyl, (C 1 to C 10 alkyl) naphthyl, (C 1 to C 10 alkenyl) naphthyl, phenyl (C 1 to C 10 alkyl), phenyl (C 1 to C 10 alkenyl), naphthyl (C 1 to C 10 alkyl) and naphthyl (C 1 to C 10 alkenyl);
- R 9 is optionally substituted with C 1 to C 4 alkyl, C 1 to C 4 alkenyl, C 1 to C 4 alkoxy, —OH, —SH and —CO 2 R 11 , cycloalkyl, cycloalkenyl, heterocyclic alkyl, alkaryl, heteroaryl, heteroalkaryl, or any combination thereof;
- R 11 is hydrogen, C 1 to C 4 alkyl or C 1 to C 4 alkenyl
- R 9 is optionally interrupted by oxygen, nitrogen, sulfur or any combination thereof.
- R 10 is hydrogen, C 1 to C 4 alkyl or C 1 to C 4 alkenyl.
- R 12 is (i) C 3 -C 10 cycloalkyl, optionally substituted with C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 1 -C 7 alkoxy, hydroxy, phenyl, phenoxy or —CO 2 R 15 , wherein R 15 is hydrogen, C 1 -C 4 alkyl, or C 2 -C 4 alkenyl; or
- R 13 is hydrogen, C 1 -C 4 alkyl, or C 2 -C 4 alkenyl
- R 14 is C 1 -C 24 alkyl, C 2 -C 24 alkenyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, phenyl, naphthyl, (C 1 -C 10 alkyl) phenyl, (C 2 -C 10 alkenyl) phenyl, (C 1 -C 10 alkyl) naphthyl, (C 2 -C 10 alkenyl) naphthyl, phenyl (C 1 -C 10 alkyl), phenyl (C 2 -C 10 alkenyl), naphthyl (C 1 -C 10 alkyl) or naphthyl (C 2 -C 10 alkenyl);
- R 14 being optionally substituted with C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, —OH, —SH, —CO 2 R 16 , C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkenyl, heterocycle having 3-10 ring atoms wherein the hetero atom is one or more of N, O, S or any combination thereof, aryl, (C 1 -C 10 alk)aryl, ar(C 1 -C 10 alkyl), or any combination thereof;
- R 14 being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof;
- R 16 is hydrogen, C 1 -C 4 alkyl, or C 2 -C 4 alkenyl.
- Acylated amino acids may be prepared by reacting single amino acids, mixtures of two or more amino acids, or amino acid esters with an amine modifying agent which reacts with free amino moieties present in the amino acids to form amides.
- Suitable, but non-limiting, examples of acylating agents useful in preparing acylated amino acids include
- R 17 an appropriate group for the modified amino acid being prepared, such as, but not limited to, alkyl, alkenyl, cycloalkyl, or aromatic, and particularly methyl, ethyl, cyclohexyl, cyclophenyl, phenyl, or benzyl, and X is a leaving group.
- Typical leaving groups include, but are not limited to, halogens such as chlorine, bromine and iodine.
- acylating agents include, but are not limited to, acyl halides including, but not limited to, acetyl chloride, propyl chloride, cyclohexanoyl chloride, cyclopentanoyl chloride, and cycloheptanoyl chloride, benzoyl chloride, hippuryl chloride and the like; and anhydrides, such as acetic anhydride, propyl anhydride, cyclohexanoic anhydride, benzoic anhydride, hippuric anhydride and the like.
- acyl halides including, but not limited to, acetyl chloride, propyl chloride, cyclohexanoyl chloride, cyclopentanoyl chloride, and cycloheptanoyl chloride, benzoyl chloride, hippuryl chloride and the like
- anhydrides such as acetic anhydride, propyl anhydride, cyclohexanoic anhydride
- Preferred acylating agents include benzoyl chloride, hippuryl chloride, acetyl chloride, cyclohexanoyl chloride, cyclopentanoyl chloride, and cycloheptanoyl chloride.
- the amine groups can also be modified by the reaction of a carboxylic acid with coupling agents such as the carbodiimide derivatives of amino acids, particularly hydrophilic amino acids such as phenylalanine, tryptophan, and tyrosine. Further examples include dicyclohexylcarbodiimide and the like.
- amino acid is multifunctional, i.e. has more than one —OH, —NH 2 or —SH group, then it may optionally be acylated at one or more functional groups to form, for example, an ester, amide, or thioester linkage.
- acylated poly amino acids one or more of the amino acids may be modified (acylated).
- Modified poly amino acids may include one or more acylated amino acid(s).
- linear modified poly amino acids will generally include only one acylated amino acid, other poly amino acid configurations can include more than one acylated amino acid.
- Poly amino acids can be polymerized with the acylated amino acid(s) or can be acylated after polymerization.
- Sulfonated amino acids and poly amino acids are modified by sulfonating at least one free amine group with a sulfonating agent which reacts with at least one of the free amine groups present.
- Ar 3 is a substituted or unsubstituted phenyl or naphthyl
- R 19 is C 1 to C 24 alkyl, C 1 to C 24 alkenyl, phenyl, naphthyl, (C 1 to C 10 alkyl) phenyl, (C 1 to C 10 alkenyl) phenyl, (C 1 to C 10 alkyl) naphthyl, (C 1 to C 10 alkenyl) naphthyl, phenyl (C 1 to C 10 alkyl), phenyl (C 1 to C 4 alkenyl), naphthyl (C 1 to C 10 alkyl) and naphthyl (C 1 to C 10 alkenyl);
- R 19 is optionally substituted with C 1 to C 4 alkyl, C 1 to C 4 alkenyl, C 1 to C 4 alkoxy, —OH, —SH and —CO 2 R 21 or any combination thereof;
- R 21 is hydrogen, C 1 to C 4 alkyl or C 1 to C 4 alkenyl
- R 19 is optionally interrupted by oxygen, nitrogen, sulfur or any combination thereof.
- R 20 is hydrogen, C 1 to C 4 alkyl or C 1 to C 4 alkenyl.
- Suitable, but non-limiting, examples of sulfonating agents useful in preparing sulfonated amino acids include sulfonating agents having the formula R 22 —So 2 —X wherein R 22 is an appropriate group for the modified amino acid being prepared such as, but not limited to, alkyl, alkenyl, cycloalkyl, or aromatics and X is a leaving group as described above.
- R 22 is an appropriate group for the modified amino acid being prepared such as, but not limited to, alkyl, alkenyl, cycloalkyl, or aromatics and X is a leaving group as described above.
- a sulfonating agent is benzene sulfonyl chloride.
- Modified poly amino acids and peptides may include one or more sulfonated amino acid(s). Although linear modified poly amino acids and peptides used generally include only one sulfonated amino acid, other poly amino acid and peptide configurations can include more than one sulfonated amino acid. Poly amino acids and peptides can be polymerized with the sulfonated amino acid(s) or can be sulfonated after polymerization.
- Proteins are naturally occurring (i.e. not artificial) polymers of amino acids.
- Enteric coating materials known to those skilled in the art such as, for example, cellulose acetate trimellitate (CAT) and cellulose acetate phthalate (CAP), are suitable for use in the preservation as well.
- CAT cellulose acetate trimellitate
- CAP cellulose acetate phthalate
- These carriers, and particularly proteinoids, acylated amino acids or poly amino acids, sulfonated amino acids or poly amino acids, and proteins are often insoluble or relatively insoluble in neutral or mildly acidic solutions but are also soluble, as are the imidazole derivatives useful in the present invention, in aqueous acid solutions wherein the volume to volume ratio of acid to water is greater than about 3:7.
- Suitable aqueous acid solvents are as above, i.e. volatile organic acids, such as for example, aqueous acetic acid, aqueous formic acid, and the like.
- Microsphere formation occurs when the concentration of the acid in the carrier/active agent solution is decreased. As this solution is nebulized, the acid evaporates, decreasing the concentration of the acid in solution to less than 30% by volume. The carrier, then, will self assemble to form microspheres containing any optional active agent. The cargo must be stable in the concentrated acid for the time and conditions necessary to carry out the operation. Alternately, the carrier solution can be diluted, such as with water, whereby the acid concentration is decreased and the carrier precipitates to form microspheres. Preferably, the microspheres are prepared by spray drying.
- the microspheres can be pH adapted by using base or acid soluble coatings including, but not limited to, proteinoid coatings, enteric coatings, acylated amino acid coatings, and the like.
- any of the solutions above may optionally contain additives such as stabilizing additives.
- additives such as stabilizing additives.
- the presence of such additives promotes the stability and dispersability of the active agent in solution.
- the stabilizing additives may be employed at a concentration ranging between about 0.1 and 5% (w/v), preferably about 0.5% (w/v).
- Suitable, but non-limiting examples of stabilizing additives include buffer salts, gum acacia, gelatin, methyl cellulose, polyethylene glycol, and polylysine.
- the amount of active agent that may be incorporated in the microsphere is dependent upon a number of factors which include the concentration of active agent in the solution as well as the affinity of the active agent for the carrier.
- concentration of the active agent in the final formulation also will vary depending on the required amounts for any particular end use. When necessary, the exact concentration can be determined by, for example, reverse phase HPLC analysis.
- microspheres and, therefore, the solutions described above may also include one or more enzyme inhibitors.
- enzyme inhibitors include, but are not limited to, compounds such as actinonin or epiactinonin and derivatives thereof.
- the microspheres are particularly useful for administering itraconazole derivatives to any animals, including but not limited to, birds and mammals, such as primates and particularly humans; and insects.
- These microsphere systems are particularly advantageous for delivering these active agents as the active agent would otherwise be destroyed or rendered less effective by conditions encountered before the microsphere reaches the active agent target zone (i.e., the area in which the active agent of the delivery composition are to be released) and within the body of the animal to which they are administered.
- these microspheres can deliver relatively high amounts of the imidazole derivative and retain a high bioavailability.
- Acetic acid solutions were prepared in water to 10%, 20%, 50% and 75% concentrations (expressed as volume glacial acetic acid/total volume of solution ⁇ 100). 100 mg itraconazole solute were then mixed independently with 1 ml of each solution and visually monitored for dissolution. If necessary, additional 1 ml aliquots of each acetic acid solution were added until the itraconazole solute was dissolved.
- Stable proteinoid microspheres containing itraconazole were formed. Analysis of typical microspheres using RP-HPLC demonstrated that they contained 14-21% itraconazole by weight.
- FIGS. 1 A- 1 H Scanning electron microscopy in FIGS. 1 A- 1 H illustrates that the microspheres were smooth and spherical and had diameters ranging from 0.1 ⁇ m to about 5 ⁇ m. When mechanically crushed only the larger spheres shattered, while the smaller spheres remained intact. Crushing revealed a solid internal structure. See, FIGS. 1G and 1H.
Abstract
Methods for preparing microspheres containing imidazole derivatives are provided. Also provided is the use of imidazole derivatives containing microspheres for treating fungal infections. Oral dosage forms for oral administration are also provided.
Description
- The present invention relates to the preparation of solutions containing imidazole derivatives and to the use of those solutions in the preparation of microspheres. The imidazole derivative containing microspheres are effective in treating fungal infections, particularly in mammals. The microspheres facilitate the oral administration of relatively large amounts of the imidazole derivative, with increased bioavailability.
- Many present systems for delivering active agents to targets are severely limited by biological, chemical, and physical barriers, which are imposed by the environment through which delivery occurs, the environment of the target itself, or the target itself. Delivery is also limited, in many instances, by the chemical nature of the active agent. For example, oral delivery is generally ineffective with active agents that are poorly water-soluble.
- The imidazole derivative family of compounds is particularly effective against a broad range of fungal infections such as those caused byTrichophyton rubrum, Tricophyton mentagrophytes, Epidermophyton flocesum, and Candida albicans, but these compounds are either partially water soluble or insoluble in water. For example, the solubility of itraconazole in water is less than 0.00001 g/ml.
- Partially because imidazole derivatives are typically insoluble in water, they are difficult to administer orally. Consequently although imidazole derivatives are frequently prescribed for the treatment of fungal infections, they have been available only in topical preparations or in oral formulations with limited bioavailability.
- In recent years, fungal infections, such as those caused byCandida albicans in particular have become more prevalent and intractable due to their appearance in immunocompromised patients, such as those infected with Human Immunodeficiency Virus (HIV) or those suffering from Acquired Immunodeficiency Syndrome (AIDS).
- For example, U.S. Pat. No. 3,717,655 discloses imidazole derivatives which have antifungal and antibacterial activity. These compounds are almost insoluble in aqueous solutions such as water and are very poorly soluble in polar solvents such as ethanol.
- Das et al., U.S. Pat. No. 4,912,124, disclose a solvent system for imidazole derivatives that include mixtures of a polar solvent, a polyhydric alcohol that acts as a solubilizing agent, a nonionic or amphoteric surfactant, and a cosmetic humectant. Solutions containing at least 1 percent by weight of the imidazole derivatives can be formulated using this solvent system. However, these formulations are suitable for external topical use only.
- Accordingly, there is a need for orally deliverable forms of imidazole derivative antifungal agents.
- The present invention provides solutions comprising:
- (a) at least about 2.5 parts by weight, based upon 100 parts by weight of solution, of a solute having the formula
- wherein R, R1, and R2 are independently hydrogen or lower alkyl;
- R3 is hydrogen, methyl or ethyl;
- R4 is hydrogen or methyl
- Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;
- Ar1 is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl; and
- n is 1 or 2; and
- (b) a solubilizing effective amount of a solvent comprising at least one volatile organic acid solvent.
- Imidazole derivative microspheres are also provided. These microspheres comprise:
-
- wherein R, R1, and R2 are independently hydrogen or lower alkyl;
- R3 is hydrogen, methyl or ethyl;
- R4 is hydrogen or methyl
- Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;
- Ar1 is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl; and
- n is 1 or 2; and
- (b) a microsphere forming carrier selected from the group consisting of
- (i) a proteinoid;
- (ii) an acylated amino acid, poly amino acid, or a salt thereof;
- (iii) an sulfonated amino acid, poly amino acid, or a salt thereof;
- (iv) a protein or a salt thereof;
- (v) an enteric coating material; or
- (vi) any combination thereof.
- Also contemplated by the present invention is a method for preparing these microspheres. The method comprises:
- (A) nebulizing a solution comprising
-
- wherein R, R1, and R2 are independently hydrogen or lower alkyl;
- R3 is hydrogen, methyl or ethyl;
- R4 is hydrogen or methyl
- Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;
- Ar1 is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl; and
- n is 1 or 2;
- (b) an active agent and carrier solubilizing effective amount of a solvent comprising an aqueous solution of at least one volatile organic solvent; and wherein the volume:volume ratio of acid to water in said carrier solution is at least about 3:7, and
- (c) microsphere forming a carrier selected from the group consisting of
- (i) a proteinoid;
- (ii) an acylated amino acid or poly amino acid or a salt thereof;
- (iii) an sulfonated amino acid or poly amino acid or a salt thereof;
- (iv) a protein or a salt thereof;
- (v) an enteric coating material; or
- (vi) any combination thereof; and
- (B) decreasing said ratio to less than about 3:7, to yield said microspheres. Alternatively, the active agent and the carrier can be solubilized in separate solutions. The separate solutions can be nebulized together and the acid to water ratio then decreased as above.
- Methods for the oral administration of imidazole derivatives are also contemplated wherein the microsphere compositions above are orally administered to an animal in need of this treatment.
- FIGS.1A-1H are scanning electron microspheres of itraconazole containing microspheres prepared according to the present invention.
- It has now been discovered that water insoluble or partially soluble imidazole derivatives can be solubilized in volatile organic acids. The resultant solutions can be used to prepare imidazole containing microspheres which are suitable for oral administration to animals.
- Imidazole Derivatives
-
- wherein R, R1 and R2 are independently hydrogen or lower alkyl;
- R3 is hydrogen, methyl or ethyl;
- R4 is hydrogen or methyl
- Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono (lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;
- Ar1 is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl; and
- n is 1 or 2.
- A preferred imidazole derivative is itraconazole. Itraconazole is a synthetic triazole imidazole derivative 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers (Physicians Desk Reference 48th Ed., pg. 1097, 1994).
- Imidazole Derivative Solutions
- The solutions prepared in accordance with the present invention allow for the solubilization of imidazole derivatives at concentrations suitable for processing into orally administrable forms having acceptable bioavailability.
- In accordance with the present invention, imidazole derivatives are solubilized in volatile organic acid solvent(s). Preferred acid solvents for the imidazole derivatives are acetic acid and formic acid. Preferably, the solvent itself is an aqueous solution of the acid. Most preferably the volume:volume ratio of the acid to the total volume of the solvent is 3:7 or greater. It has been found that by using this solvent system up to a 50% solution of imidazole derivative can be prepared.
- Dissolution is achieved by simple mixing, with heating if necessary. The more concentrated the acid in the solvent, the greater the amount of active agent that can be incorporated into the solution. If lower concentrations of acid are required for the end use of the solution, the active agent can first be dissolved in a more concentrated acid solution, and the resultant solution then slowly diluted further, preferably with water.
- Preferably, the solution comprises from about 3 to about 40 percent by weight of solute and from about 60 to about 97 parts by weight of solvent based upon 100 parts by weight of solution.
- The solvent itself, preferably comprises from about 30 to about 80 parts by volume of acid and from about 70 to about 20 parts by volume of water based upon 100 parts by volume of solvent. Most preferably, the solvent comprises from about 40 to about 50 parts by volume of acid and from about 60 to about 50 parts by volume of water based upon 100 parts by volume of solvent.
- Microspheres
- Microspheres are useful in the delivery of active agents because they protect an active agent cargo until it is delivered to a target. Microspheres are particularly useful in the oral delivery of biologically active agents such as, for example, pharmaceutically active agents. Copending Application entitled “Method of Solubilizing and Encapsulating Itraconazole”, filed on [. . . ] discloses methods and apparatus for forming microspheres.
- Microspheres containing an active agent can be generally of the matrix form or the capsule form. In a hollow matrix spheroid form, the center of the sphere is hollow and the cargo or active agent is distributed throughout a carrier matrix. In a solid matrix form, the carrier matrix forms a continuum in which the cargo is distributed. In the microcapsule form, the encapsulated material or cargo can be either in solution or a solid, with the carrier forming a shell around the cargo.
- The methods of the present invention are cost-effective for preparing microspheres which contain imidazole derivatives, are simple to perform, and are amenable to industrial scale-up for commercial production.
- Carriers
- Carriers suitable for use in the present invention are microsphere forming carriers. These carriers include, without limitation, proteinoids; acylated amino acids, poly amino acids or salts thereof; sulfonated amino acids, poly amino acids or salts thereof; proteins or salts thereof, enteric coating materials; or any combination thereof.
- Amino acids are the basic materials used to prepare many of the carriers useful in the present invention. Amino acids include any carboxylic acid having at least one free amino group and include naturally occurring and synthetic amino acids. The preferred amino acids for use in the present invention are ∝-amino acids and, most preferably, are naturally occurring ∝-amino acids. Many amino acids and amino acid esters are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, Wis., USA); Sigma Chemical Co. (St. Louis, Mo., USA); and Fluka Chemical Corp. (Ronkonkoma, N.Y., USA).
-
- wherein:
- R5 is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl;
- R6 is C1-C24 alkyl, C2-C24 alkenyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, phenyl, naphthyl, (C1-C10 alkyl) phenyl, (C2-C10 alkenyl) phenyl, (C1-C10 alkyl) naphthyl, (C2-C10 alkenyl) naphthyl, phenyl (C1-C10 alkyl), phenyl (C2-C10 alkenyl), naphthyl (C1-C10 alkyl), or naphthyl (C2-C10 alkenyl);
- R6 being optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, —OH, —SH, —CO2R7, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocycle having 3-10 ring atoms wherein the hetero atom is one or more of N, O, S, or any combination thereof, aryl, (C1-C10 alk)aryl, ar(C1-C10 alkyl) or any combination thereof;
- R6 being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and
- R7 is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl.
- The preferred naturally occurring amino acids for use in the present invention as amino acids or components of a peptide are alanine, arginine, asparagine, aspartic acid, citrulline cysteine, cystine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, hydroxyproline, β-carboxyglutamic acid, γ-carboxyglutamic acid, phenylglycine, or O-phosphoserine. The most preferred amino acids are arginine, leucine, lysine, phenylalanine, tyrosine, tryptophan, valine, and phenylglycine.
- The preferred non-naturally occurring amino acids for use in the present invention are β-alanine, α-amino butyric acid, γ-amino butyric acid, γ-(aminophenyl) butyric acid, α-amino isobutyric acid, ε-amino caproic acid, 7-amino heptanoic acid, β-aspartic acid, aminobenzoic acid, aminophenyl acetic acid, aminophenyl butyric acid, γ-glutamic acid, cysteine (ACM), ε-lysine, methionine sulfone, norleucine, norvaline, ornithine, d-ornithine, p-nitro-phenylalanine, hydroxy proline, 1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, and thioproline.
- Poly amino acids are either peptides or two or more amino acids linked by a bond formed by other groups which can be linked, e.g., an ester or an anhydride linkage. Special mention is made of non-naturally occurring poly amino acids and particularly non-naturally occurring hetero-poly amino acids, i.e. of mixed amino acids.
- Peptides are two or more amino acids joined by a peptide bond. Peptides can vary in length from di-peptides with two amino acids to polypeptides with several hundred amino acids. See, Walker,Chambers Biological Dictionary, Cambridge, England: Chambers Cambridge, 1989, page 215. Special mention is made of non-naturally occurring peptides and particularly non-naturally occurring peptides of mixed amino acids. Special mention is also made of di-peptides tri-peptides, tetra-peptides, and penta-peptides, and particularly, the preferred peptides are di-peptides and tri-peptides. Peptides can be homo- or hetero- peptides and can include natural amino acids, synthetic amino acids, or any combination thereof.
- Proteinoids
- Proteinoids are artificial polymers of amino acids. Proteinoids preferably are prepared from mixtures of amino acids. Preferred proteinoids are condensation polymers, and most preferably, are thermal condensation polymers. These polymers may be directed or random polymers. Proteinoids can be linear, branched, or cyclical, and certain proteinoids can be units of other linear, branched, or cyclical proteinoids.
- Special mention is made of diketopiperazines. Diketopiperazines are six member ring compounds. The ring includes two nitrogen atoms and is substituted at two carbons with two oxygen atoms. Preferably, the carbonyl groups are at the 2 and 5 ring positions. These rings can be optionally, and most often are, further substituted.
- Diketopiperazine ring systems may be generated during thermal polymerization or condensation of amino acids or amino acid derivatives. (Gyore, J; Ecet M.Proceedings Fourth ICTA (Thermal Analysis), 1974, 2, 387-394 (1974)). These six membered ring systems were presumably generated by intra-molecular cyclization of the dimer prior to further chain growth or directly from a linear peptide (Reddy, A. V., Int. J. Peptide Protein Res., 40, 472-476 (1992); Mazurov, A. A. et al., Int. J. Peptide Protein Res., 42, 14-19 (1993)).
- Diketopiperazines can also be formed by cyclodimerization of amino acid ester derivatives as described by Katchalski et al.,J. Amer. Chem. Soc., 68, 879-880 (1946), by cyclization of dipeptide ester derivatives, or by thermal dehydration of amino acid derivatives and high boiling solvents as described by Kopple et al., J. Org. Chem., 33 (2), 862-864 (1968).
- Diketopiperazines typically are formed from α-amino acids. Preferably, the α-amino acids of which the diketopiperazines are derived are glutamic acid, aspartic acid, tyrosine, phenylalanine, and optical isomers of any of the foregoing.
- Modified Amino Acids and Poly Amino Acids
- Modified amino acids, poly amino acids, or peptides are either acylated or sulfonated and include amino acid amides and sulfonamides.
- Acylated Amino Acids and Poly Amino Acids
- Although any acylated amino acids or poly amino acids are useful in the present invention, special mention is made of acylated amino acids having the formula
- Ar2—Y—(R8)n—OH III
- wherein Ar2 is a substituted or unsubstituted phenyl or naphthyl;
-
-
- wherein:
- R9 is C1 to C24 alkyl, C1 to C24 alkenyl, phenyl, naphthyl, (C1 to C10 alkyl) phenyl, (C1 to C10 alkenyl) phenyl, (C1 to C10 alkyl) naphthyl, (C1 to C10 alkenyl) naphthyl, phenyl (C1 to C10 alkyl), phenyl (C1 to C10 alkenyl), naphthyl (C1 to C10 alkyl) and naphthyl (C1 to C10 alkenyl);
- R9 is optionally substituted with C1 to C4 alkyl, C1 to C4 alkenyl, C1 to C4 alkoxy, —OH, —SH and —CO2R11, cycloalkyl, cycloalkenyl, heterocyclic alkyl, alkaryl, heteroaryl, heteroalkaryl, or any combination thereof;
- R11 is hydrogen, C1 to C4 alkyl or C1 to C4 alkenyl;
- R9 is optionally interrupted by oxygen, nitrogen, sulfur or any combination thereof; and
- R10 is hydrogen, C1 to C4 alkyl or C1 to C4 alkenyl.
-
- wherein:
- R12 is (i) C3-C10 cycloalkyl, optionally substituted with C1-C7 alkyl, C2-C7 alkenyl, C1-C7 alkoxy, hydroxy, phenyl, phenoxy or —CO2R15, wherein R15 is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl; or
- (ii) C1-C6 alkyl substituted with C3-C10 cycloalkyl;
- R13 is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl;
- R14 is C1-C24 alkyl, C2-C24 alkenyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, phenyl, naphthyl, (C1-C10 alkyl) phenyl, (C2-C10 alkenyl) phenyl, (C1-C10 alkyl) naphthyl, (C2-C10 alkenyl) naphthyl, phenyl (C1-C10 alkyl), phenyl (C2-C10 alkenyl), naphthyl (C1-C10 alkyl) or naphthyl (C2-C10 alkenyl);
- R14 being optionally substituted with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, —OH, —SH, —CO2R16, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocycle having 3-10 ring atoms wherein the hetero atom is one or more of N, O, S or any combination thereof, aryl, (C1-C10 alk)aryl, ar(C1-C10 alkyl), or any combination thereof;
- R14 being optionally interrupted by oxygen, nitrogen, sulfur, or any combination thereof; and
- R16 is hydrogen, C1-C4 alkyl, or C2-C4 alkenyl.
- Acylated amino acids may be prepared by reacting single amino acids, mixtures of two or more amino acids, or amino acid esters with an amine modifying agent which reacts with free amino moieties present in the amino acids to form amides.
- Suitable, but non-limiting, examples of acylating agents useful in preparing acylated amino acids include
-
- wherein:
- R17 an appropriate group for the modified amino acid being prepared, such as, but not limited to, alkyl, alkenyl, cycloalkyl, or aromatic, and particularly methyl, ethyl, cyclohexyl, cyclophenyl, phenyl, or benzyl, and X is a leaving group. Typical leaving groups include, but are not limited to, halogens such as chlorine, bromine and iodine.
- Examples of the acylating agents include, but are not limited to, acyl halides including, but not limited to, acetyl chloride, propyl chloride, cyclohexanoyl chloride, cyclopentanoyl chloride, and cycloheptanoyl chloride, benzoyl chloride, hippuryl chloride and the like; and anhydrides, such as acetic anhydride, propyl anhydride, cyclohexanoic anhydride, benzoic anhydride, hippuric anhydride and the like. Preferred acylating agents include benzoyl chloride, hippuryl chloride, acetyl chloride, cyclohexanoyl chloride, cyclopentanoyl chloride, and cycloheptanoyl chloride.
- The amine groups can also be modified by the reaction of a carboxylic acid with coupling agents such as the carbodiimide derivatives of amino acids, particularly hydrophilic amino acids such as phenylalanine, tryptophan, and tyrosine. Further examples include dicyclohexylcarbodiimide and the like.
- If the amino acid is multifunctional, i.e. has more than one —OH, —NH2 or —SH group, then it may optionally be acylated at one or more functional groups to form, for example, an ester, amide, or thioester linkage.
- In acylated poly amino acids, one or more of the amino acids may be modified (acylated). Modified poly amino acids may include one or more acylated amino acid(s). Although linear modified poly amino acids will generally include only one acylated amino acid, other poly amino acid configurations can include more than one acylated amino acid. Poly amino acids can be polymerized with the acylated amino acid(s) or can be acylated after polymerization.
- Sulfonated Amino Acids and Poly Amino Acids
- Sulfonated amino acids and poly amino acids are modified by sulfonating at least one free amine group with a sulfonating agent which reacts with at least one of the free amine groups present.
- Special mention is made of compounds of the formula
- Ar3—Y—(R18)n—OH V
- wherein Ar3 is a substituted or unsubstituted phenyl or naphthyl;
-
- wherein:
- R19 is C1 to C24 alkyl, C1 to C24 alkenyl, phenyl, naphthyl, (C1 to C10 alkyl) phenyl, (C1 to C10 alkenyl) phenyl, (C1 to C10 alkyl) naphthyl, (C1 to C10 alkenyl) naphthyl, phenyl (C1 to C10 alkyl), phenyl (C1 to C4 alkenyl), naphthyl (C1 to C10 alkyl) and naphthyl (C1 to C10 alkenyl);
- R19 is optionally substituted with C1 to C4 alkyl, C1 to C4 alkenyl, C1 to C4 alkoxy, —OH, —SH and —CO2R21 or any combination thereof;
- R21 is hydrogen, C1 to C4 alkyl or C1 to C4 alkenyl;
- R19 is optionally interrupted by oxygen, nitrogen, sulfur or any combination thereof; and
- R20 is hydrogen, C1 to C4 alkyl or C1 to C4 alkenyl.
- Suitable, but non-limiting, examples of sulfonating agents useful in preparing sulfonated amino acids include sulfonating agents having the formula R22—So2—X wherein R22 is an appropriate group for the modified amino acid being prepared such as, but not limited to, alkyl, alkenyl, cycloalkyl, or aromatics and X is a leaving group as described above. One example of a sulfonating agent is benzene sulfonyl chloride.
- Modified poly amino acids and peptides may include one or more sulfonated amino acid(s). Although linear modified poly amino acids and peptides used generally include only one sulfonated amino acid, other poly amino acid and peptide configurations can include more than one sulfonated amino acid. Poly amino acids and peptides can be polymerized with the sulfonated amino acid(s) or can be sulfonated after polymerization.
- Proteins
- Proteins are naturally occurring (i.e. not artificial) polymers of amino acids.
- Enteric Coating Materials
- Enteric coating materials known to those skilled in the art such as, for example, cellulose acetate trimellitate (CAT) and cellulose acetate phthalate (CAP), are suitable for use in the preservation as well.
- Formation
- These carriers, and particularly proteinoids, acylated amino acids or poly amino acids, sulfonated amino acids or poly amino acids, and proteins are often insoluble or relatively insoluble in neutral or mildly acidic solutions but are also soluble, as are the imidazole derivatives useful in the present invention, in aqueous acid solutions wherein the volume to volume ratio of acid to water is greater than about 3:7. Suitable aqueous acid solvents are as above, i.e. volatile organic acids, such as for example, aqueous acetic acid, aqueous formic acid, and the like. These acids will volatilize upon nebulization or can be diluted in the aqueous solution, thereby decreasing the concentration of the acid and reversing the solubility of the carrier even in the absence of a precipitator. For example, see currently filed U.S. patent application Ser. No. ______ , (attorney's docket no. 1946/09202) entitled “SPRAY DRYING METHOD AND APPARATUS”.
- Microsphere formation occurs when the concentration of the acid in the carrier/active agent solution is decreased. As this solution is nebulized, the acid evaporates, decreasing the concentration of the acid in solution to less than 30% by volume. The carrier, then, will self assemble to form microspheres containing any optional active agent. The cargo must be stable in the concentrated acid for the time and conditions necessary to carry out the operation. Alternately, the carrier solution can be diluted, such as with water, whereby the acid concentration is decreased and the carrier precipitates to form microspheres. Preferably, the microspheres are prepared by spray drying.
- The microspheres can be pH adapted by using base or acid soluble coatings including, but not limited to, proteinoid coatings, enteric coatings, acylated amino acid coatings, and the like.
- Any of the solutions above may optionally contain additives such as stabilizing additives. The presence of such additives promotes the stability and dispersability of the active agent in solution. The stabilizing additives may be employed at a concentration ranging between about 0.1 and 5% (w/v), preferably about 0.5% (w/v). Suitable, but non-limiting examples of stabilizing additives include buffer salts, gum acacia, gelatin, methyl cellulose, polyethylene glycol, and polylysine.
- The amount of active agent that may be incorporated in the microsphere is dependent upon a number of factors which include the concentration of active agent in the solution as well as the affinity of the active agent for the carrier. The concentration of the active agent in the final formulation also will vary depending on the required amounts for any particular end use. When necessary, the exact concentration can be determined by, for example, reverse phase HPLC analysis.
- The microspheres and, therefore, the solutions described above may also include one or more enzyme inhibitors. Such enzyme inhibitors include, but are not limited to, compounds such as actinonin or epiactinonin and derivatives thereof.
- The microspheres are particularly useful for administering itraconazole derivatives to any animals, including but not limited to, birds and mammals, such as primates and particularly humans; and insects. These microsphere systems are particularly advantageous for delivering these active agents as the active agent would otherwise be destroyed or rendered less effective by conditions encountered before the microsphere reaches the active agent target zone (i.e., the area in which the active agent of the delivery composition are to be released) and within the body of the animal to which they are administered. Furthermore, these microspheres can deliver relatively high amounts of the imidazole derivative and retain a high bioavailability.
- The following examples illustrate the present invention without limitation.
- Acetic acid solutions were prepared in water to 10%, 20%, 50% and 75% concentrations (expressed as volume glacial acetic acid/total volume of solution×100). 100 mg itraconazole solute were then mixed independently with 1 ml of each solution and visually monitored for dissolution. If necessary, additional 1 ml aliquots of each acetic acid solution were added until the itraconazole solute was dissolved.
- Results are illustrated in Table 1 below. The solubilized material did not precipitate readily.
TABLE 1 SOLUBILITY Concentration Amount of Solvent of Acid 1 ml 1 ml 2 ml 2 ml 3 ml 3 ml 4 ml 4 ml in Solvent Cold Hot Cold Hot Cold Hot Cold Hot 10% Acetic Ins. Ins. Ins. Ins. Ins. Ins. — Ins. Acid v:v 20% Acetic Ins. Ins. Ins. Ins. Ins. Part — — Acid v:v Sol. 50% Acetic Ins. Ins. Ins. Sol. Ins. — — — Acid v:v 75% Acetic Sol. — — — — — — — Acid v:v - 100 mg of itraconazole solute were dissolved in 1 ml glacial acetic acid solvent and aqueous acetic acid solvent at various concentrations. Results are illustrated in Table 2 below.
TABLE 2 ITRACONAZOLE SOLUTE % Acetic Acid (v:v) Dissolved Itraconazole % 100 >33 (dissolves freely on addition) 75 >10 (dissolves freely on addition) 40 5 (diss.conc.acid, then dilute) 20 2.5 (diss.conc.acid, then dilute) - 60 grams of itraconazole solute (Janssen Pharmaceutica) were added to 1.43 liters of glacial acetic acid solvent, and the mixture was stirred to dissolve the solute. 1.43 liters of water were then added using a pump at a flow rate of 25 ml/min. Slight clouding of the solution was observed, but cleared upon further stirring. 166 grams of proteinoid (Glu-Asp-Tyr-Phe-Orn) were added and dissolved with further stirring. The final solution was filtered through folded tissue paper.
- Using peristaltic pumps, the solution was fed through a Virtis SD04 spray drying apparatus under the conditions of Table 3 below.
TABLE 3 SPRAY DRYING CONDITIONS Solution flow rate 7-8 ml/min Inlet temperature 175° C. Outlet temperature 116° C. Blower speed full Compressor pressure full - Stable proteinoid microspheres containing itraconazole were formed. Analysis of typical microspheres using RP-HPLC demonstrated that they contained 14-21% itraconazole by weight.
- Scanning electron microscopy in FIGS.1A-1H illustrates that the microspheres were smooth and spherical and had diameters ranging from 0.1 μm to about 5 μm. When mechanically crushed only the larger spheres shattered, while the smaller spheres remained intact. Crushing revealed a solid internal structure. See, FIGS. 1G and 1H.
- All patents, applications, publications, and test methods mentioned herein are hereby incorporated by reference in their entirety.
- Many variations of the present invention will suggest themselves to those skilled in the art in light of the above-detailed description in which obvious variations are within the full intended scope of the appended claims.
Claims (20)
1. A solution comprising:
(a) at least about 2.5 parts by weight, based upon 100 parts by weight of solution, of a solute having the formula
wherein R, R1, and R 2 are independently hydrogen or lower alkyl;
R3 is hydrogen, methyl or ethyl;
R4 is hydrogen or methyl
Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;
Ar1 is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl; and
n is 1 or 2; and
(b) a solubilizing effective amount of a solvent comprising at least one volatile organic acid.
2. A solution as defined in claim 1 , wherein said solute comprises itraconazole.
3. A solution as defined in claim 1 , wherein said solvent comprises an aqueous solution of said acid.
4. A solution as defined in claim 3 , wherein said solvent comprises aqueous acetic acid.
5. A solution is defined as in claim 3 , wherein said solvent comprises aqueous formic acid.
6. A solution is defined in claim 1 , wherein said solution comprises from about 3 to about 40 percent by weight of solute and from about 60 to about 97 parts by weight of solvent based upon 100 parts by weight of solution.
7. A solution as defined in claim 3 , wherein said solvent comprises from about 30 to about 80 parts by volume of acid and from about 70 to about 20 parts by volume of water, based upon 100 parts by volume of solvent.
8. A solution as defined in claim 7 , wherein said solvent comprises from about 40 to about 50 parts by volume weight of acid and from about 60 to about 50 parts by volume of water, based upon 100 parts by volume of solvent.
9. A solution is defined in claim 3 , wherein the volume:volume ratio of acid to water in said solvent is at least about 3:7.
10. A microsphere comprising
(a) an imidazole derivative active agent having the formula
wherein R, R1, and R2 are independently hydrogen or lower alkyl;
R3 is hydrogen, methyl or ethyl;
R4 is hydrogen or methyl
Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;
Ar1 is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl; and
n is 1 or 2; and
(b) a microsphere forming carrier selected from the group consisting of
(i) a proteinoid;
(ii) an acylated amino acid or poly amino acid or a salt thereof;
(iii) a sulfonated amino acid or poly amino acid or a salt thereof;
(iv) a protein or a salt thereof;
(v) an enteric coating material; or
(vi) any combination thereof.
11. A microsphere as defined in claim 10 , wherein said imidazole derivative active agent comprises itraconazole.
12. A method for preparing imidazole derivative active agent containing microspheres, said method comprising
(A) nebulizing a solution comprising
(a) an imidazole active agent having the formula
wherein R, R1, and R2 are independently hydrogen or lower alkyl;
R3 is hydrogen, methyl or ethyl;
R4 is hydrogen or methyl
Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;
Ar1 is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl; and
n is 1 or 2;
(b) a microsphere forming carrier selected from the group consisting of
(i) a proteinoid;
(ii) an acylated amino acid or poly amino acid or a salt thereof;
(iii) a sulfonated amino acid or poly amino acid or a salt thereof;
(iv) a protein or a salt thereof;
(v) an enteric coating material; or
(vi) any combination thereof; and
(c) an active agent and carrier solubilizing effective amount of a solvent comprising an aqueous solution of at least one volatile organic acid;
wherein the volume:volume ratio of acid to water in said solvent is at least about 3:7; and
(B) decreasing said ratio to less than about 3:7, to yield said microspheres.
13. A method as defined in claim 12 , wherein said imidazole derivative active agent comprises itraconazole.
14. A method as defined in claim 12 , wherein said aqueous solution comprises aqueous acetic acid.
15. A method as defined in claim 12 , wherein said nebulizing is performed by spray drying.
16. A method wherein said ratio is decreased by volatilizing at least a portion of said acid.
17. A method wherein said ratio is decreased by diluting said acid.
18. A method for preparing imidazole derivative active agent containing microspheres, said method comprising
(A) nebulizing
(a) a solution comprising
(i) an imidazole active agent having the formula
wherein R, R1, and R2 are independently hydrogen or lower alkyl;
R3 is hydrogen, methyl or ethyl;
R4 is hydrogen or methyl
Ar is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or halothienyl;
Ar1 is phenyl, monohalophenyl, dihalophenyl, trihalophenyl, mono(lower alkyl)phenyl, di(lower alkyl)phenyl, lower alkoxyphenyl, or cyanophenyl; and
n is 1 or 2; and
(ii) an active agent solubilizing effective amount of a solvent comprising an aqueous solution of at least one volatile organic acid;
wherein the volume:volume ratio of acid to water in said solvent is at least about 3:7; and
(b) a solution of a microsphere forming carrier selected from the group consisting of
(i) a proteinoid;
(ii) an acylated amino acid or poly amino acid or a salt thereof;
(iii) a sulfonated amino acid or poly amino acid or a salt thereof;
(iv) a protein or a salt thereof;
(v) an enteric coating material; or
(vi) any combination thereof; and
(B) decreasing said ratio to less than about 3:7, to yield said microspheres.
19. A method for administering itraconazole to an animal in need of such treatment, such method comprising
(A) preparing a composition as defined in claim 10 , and
(B) orally administering said composition to said animal.
20. A method for treating a fungal infection in an animal in need of such treatment, said method comprising administering to said animal a therapeutically effective amount of a composition as defined in claim 10.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/222,640 US20030042638A1 (en) | 1995-06-07 | 2002-08-15 | Method of solubilizing and encapsulating itraconazole |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/475,887 US5750147A (en) | 1995-06-07 | 1995-06-07 | Method of solubilizing and encapsulating itraconazole |
US08/967,486 US6100285A (en) | 1995-06-07 | 1997-11-11 | Method of solubilizing itraconazole |
US09/478,661 US6461545B1 (en) | 1995-06-07 | 2000-01-06 | Method of solubilizing and encapsulating itraconazole |
US10/222,640 US20030042638A1 (en) | 1995-06-07 | 2002-08-15 | Method of solubilizing and encapsulating itraconazole |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/478,661 Continuation US6461545B1 (en) | 1995-06-07 | 2000-01-06 | Method of solubilizing and encapsulating itraconazole |
Publications (1)
Publication Number | Publication Date |
---|---|
US20030042638A1 true US20030042638A1 (en) | 2003-03-06 |
Family
ID=23889578
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/475,887 Expired - Lifetime US5750147A (en) | 1995-06-07 | 1995-06-07 | Method of solubilizing and encapsulating itraconazole |
US08/967,486 Expired - Lifetime US6100285A (en) | 1995-06-07 | 1997-11-11 | Method of solubilizing itraconazole |
US09/478,661 Expired - Lifetime US6461545B1 (en) | 1995-06-07 | 2000-01-06 | Method of solubilizing and encapsulating itraconazole |
US10/222,640 Abandoned US20030042638A1 (en) | 1995-06-07 | 2002-08-15 | Method of solubilizing and encapsulating itraconazole |
Family Applications Before (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/475,887 Expired - Lifetime US5750147A (en) | 1995-06-07 | 1995-06-07 | Method of solubilizing and encapsulating itraconazole |
US08/967,486 Expired - Lifetime US6100285A (en) | 1995-06-07 | 1997-11-11 | Method of solubilizing itraconazole |
US09/478,661 Expired - Lifetime US6461545B1 (en) | 1995-06-07 | 2000-01-06 | Method of solubilizing and encapsulating itraconazole |
Country Status (4)
Country | Link |
---|---|
US (4) | US5750147A (en) |
EP (1) | EP0831703A4 (en) |
AU (1) | AU6174796A (en) |
WO (1) | WO1996039835A1 (en) |
Families Citing this family (60)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6221367B1 (en) | 1992-06-15 | 2001-04-24 | Emisphere Technologies, Inc. | Active agent transport systems |
US6099856A (en) | 1992-06-15 | 2000-08-08 | Emisphere Technologies, Inc. | Active agent transport systems |
US5714167A (en) | 1992-06-15 | 1998-02-03 | Emisphere Technologies, Inc. | Active agent transport systems |
US5578323A (en) | 1992-06-15 | 1996-11-26 | Emisphere Technologies, Inc. | Proteinoid carriers and methods for preparation and use thereof |
US6916489B2 (en) * | 1992-06-15 | 2005-07-12 | Emisphere Technologies, Inc. | Active agent transport systems |
US6090925A (en) | 1993-03-09 | 2000-07-18 | Epic Therapeutics, Inc. | Macromolecular microparticles and methods of production and use |
US5981719A (en) | 1993-03-09 | 1999-11-09 | Epic Therapeutics, Inc. | Macromolecular microparticles and methods of production and use |
US20010003001A1 (en) | 1993-04-22 | 2001-06-07 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US6461643B2 (en) | 1993-04-22 | 2002-10-08 | Emisphere Technologies, Inc. | Oral drug delivery compositions and methods |
CN1151836C (en) | 1995-03-31 | 2004-06-02 | 艾米斯菲尔技术有限公司 | Compound and compositions for delivering active agents |
US5989539A (en) | 1995-03-31 | 1999-11-23 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US6090958A (en) | 1995-03-31 | 2000-07-18 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US6001347A (en) | 1995-03-31 | 1999-12-14 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5750147A (en) | 1995-06-07 | 1998-05-12 | Emisphere Technologies, Inc. | Method of solubilizing and encapsulating itraconazole |
US6051258A (en) | 1995-06-07 | 2000-04-18 | Emisphere Technologies, Inc. | Proteinoid emulsions and methods for preparation and use thereof |
WO1997010197A1 (en) | 1995-09-11 | 1997-03-20 | Emisphere Technologies, Inc. | METHOD FOR PREPARING φ-AMINOALKANOIC ACID DERIVATIVES FROM CYCLOALKANONES |
SI9720025A (en) | 1996-03-29 | 1999-08-31 | Emishphere Technologies, Inc. | Compounds and compositions for delivering active agents |
WO1997047288A1 (en) | 1996-06-14 | 1997-12-18 | Emisphere Technologies, Inc. | Microencapsulated fragrances and method for preparation |
CA2243643A1 (en) | 1996-11-18 | 1998-05-28 | Susan Haas | Methods and compositions for inducing oral tolerance in mammals |
US6313088B1 (en) | 1997-02-07 | 2001-11-06 | Emisphere Technologies, Inc. | 8-[(2-hydroxy-4-methoxy benzoyl) amino]-octanoic acid compositions for delivering active agents |
US5990166A (en) | 1997-02-07 | 1999-11-23 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US6358504B1 (en) | 1997-02-07 | 2002-03-19 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US6060513A (en) | 1997-02-07 | 2000-05-09 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5863944A (en) | 1997-04-30 | 1999-01-26 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5962710A (en) | 1997-05-09 | 1999-10-05 | Emisphere Technologies, Inc. | Method of preparing salicyloylamino acids |
KR19990001564A (en) * | 1997-06-16 | 1999-01-15 | 유충식 | Azole antifungal agents with improved solubility and preparations containing them |
WO1999017743A1 (en) * | 1997-10-07 | 1999-04-15 | Fuisz Technologies Ltd. | Dosage forms having improved release properties |
ES2185238T3 (en) | 1997-12-31 | 2003-04-16 | Choongwae Pharma Corp | ORAL PREPARATION OF ITRACONAZOL AND ITS PREPARATION PROCEDURE. |
HUP0103318A2 (en) | 1998-07-27 | 2002-01-28 | Emisphere Technologies Inc. | Process for pulmonary delivery of active agents |
US6440929B1 (en) | 1998-07-27 | 2002-08-27 | Emisphere Technologies, Inc. | Pulmonary delivery of active agents |
US6991798B1 (en) | 1998-08-07 | 2006-01-31 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
CA2339765C (en) | 1998-08-07 | 2009-04-28 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
BR0008590A (en) * | 1999-01-08 | 2001-10-30 | Emisphere Tech Inc | Polymeric delivery agent, composition, unit dosage form, method for administering a biologically active agent to an animal requiring the agent, method for preparing a composition; it's composed |
US7084279B1 (en) | 1999-02-11 | 2006-08-01 | Emisphere Technologies Inc. | Oxadiazole compounds and compositions for delivering active agents |
WO2000050386A1 (en) | 1999-02-26 | 2000-08-31 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
NZ534409A (en) * | 1999-04-05 | 2006-03-31 | Emisphere Tech Inc | Disodium salts, monohydrates, and ethanol solvates for delivering active agents |
KR100331529B1 (en) * | 1999-06-16 | 2002-04-06 | 민경윤 | Composition for Oral Administration of Hardly Soluble Antifungal Agent and Process for the Preparation Thereof |
US7279597B1 (en) | 1999-11-05 | 2007-10-09 | Emisphere Technologies, Inc. | Phenyl amine carboxylic acid compounds and compositions for delivering active agents |
US7129274B1 (en) | 1999-11-05 | 2006-10-31 | Emisphere Technologies Inc. | Phenoxy carboxylic acid compounds and compositions for delivering active agents |
CA2291346A1 (en) * | 1999-11-26 | 2001-05-26 | Bernard Charles Sherman | Antifungal solutions |
ATE387430T1 (en) | 1999-12-16 | 2008-03-15 | Emisphere Tech Inc | COMPOUNDS AND COMPOSITIONS FOR DELIVERING ACTIVE INGREDIENTS |
GB0015239D0 (en) * | 2000-06-21 | 2000-08-16 | Biochemie Gmbh | Organic compounds |
US6673373B2 (en) | 2001-02-01 | 2004-01-06 | Carlsbad Technology Inc. | Antifungal formulation and the methods for manufacturing and using the same |
US20030225300A1 (en) * | 2001-04-19 | 2003-12-04 | Emisphere Technologies Inc. | Compounds and compositions for delivering active agents |
CA2363376A1 (en) * | 2001-11-16 | 2003-05-16 | Bernard Charles Sherman | Solid pharmaceutical compositions for oral administration comprising itraconazole |
US20050074494A1 (en) * | 2003-10-06 | 2005-04-07 | Xiu-Xiu Cheng | Itraconazole immediate release formulation |
JP2005209106A (en) * | 2004-01-26 | 2005-08-04 | Nec Corp | Portable communication terminal, received e-mail management method, program and recording medium |
KR20070008720A (en) * | 2004-05-06 | 2007-01-17 | 에미스페어 테크놀로지스, 인코포레이티드 | Solid dosage form of wetted heparin |
KR101299707B1 (en) | 2004-05-14 | 2013-08-28 | 에미스페어 테크놀로지스, 인코포레이티드 | Compounds and compositions for delivering active agents |
MXPA06013295A (en) | 2004-05-19 | 2007-02-22 | Emisphere Tech Inc | Acyclovir formulations. |
US9345725B2 (en) | 2004-12-29 | 2016-05-24 | Emisphere Technologies, Inc. | Pharmaceutical formulations of gallium salts |
US8110547B2 (en) | 2005-01-12 | 2012-02-07 | Emisphere Technologies, Inc. | Compositions for buccal delivery of parathyroid hormone |
WO2007121318A2 (en) * | 2006-04-12 | 2007-10-25 | Emisphere Technologies, Inc. | Formulations for delivering insulin |
WO2007133944A2 (en) | 2006-05-09 | 2007-11-22 | Emisphere Technologies, Inc. | Topical administration of acyclovir |
WO2008003050A2 (en) * | 2006-06-28 | 2008-01-03 | Emisphere Technologies, Inc. | Gallium nitrate formulations |
US20090076028A1 (en) * | 2007-09-15 | 2009-03-19 | Protia, Llc | Deuterium-enriched itraconazole |
GB0720716D0 (en) * | 2007-10-23 | 2007-12-05 | York Pharma Plc | Novel formulation |
CN102351850A (en) * | 2009-01-14 | 2012-02-15 | 重庆华邦胜凯制药有限公司 | Method for refining itraconazole |
JP5985985B2 (en) * | 2009-08-03 | 2016-09-06 | エミスフィアー テクノロジーズ インコーポレイテッドEmisphere Technologies,Inc. | Rapid-acting naproxen composition with reduced gastrointestinal effects |
BRPI0904249B1 (en) * | 2009-08-28 | 2018-03-06 | Biolab Sanus Farmacêutica Ltda. | BENZYL ARALQUIL ETHER COMPOUNDS, PREPARATION PROCESS FOR THEM, USE OF SUCH COMPOUNDS, PHARMACEUTICAL COMPOSITION |
Family Cites Families (187)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US24899A (en) * | 1859-07-26 | Edwabd f | ||
US2671451A (en) * | 1952-06-16 | 1954-03-09 | Stephen J Bolger | Remedial pill |
BE530009A (en) | 1953-06-30 | |||
US2828206A (en) * | 1954-02-24 | 1958-03-25 | Roseuberg Adolf | Stabilized fat-soluble vitamins and methods of making same |
US2868740A (en) * | 1954-03-25 | 1959-01-13 | Swift & Co | Method of copolymerizing acrylic or methacrylic acid with proteinaceous material and product obtained |
US2862918A (en) * | 1956-03-12 | 1958-12-02 | Glidden Co | Acylated, isolated, partially-hydrolyzed, soya protein and process |
NL108169C (en) * | 1957-01-30 | |||
US3057344A (en) * | 1957-05-21 | 1962-10-09 | Abella Carlos Alberto | Capsule for the study of the digestive tract and method of using the same |
US3016308A (en) * | 1957-08-06 | 1962-01-09 | Moore Business Forms Inc | Recording paper coated with microscopic capsules of coloring material, capsules and method of making |
US3052655A (en) * | 1958-08-01 | 1962-09-04 | Sidney W Fox | Thermal polymerization of amino acid mixtures containing aspartic acid or a thermal precursor of aspartic acid |
US3076790A (en) * | 1958-08-01 | 1963-02-05 | Sidney W Fox | Method of making copolymers of amino acids containing glutamic acid |
GB929401A (en) | 1958-12-22 | 1963-06-19 | Upjohn Co | Encapsulated emulsions and processes for their preparation |
FR1468601A (en) | 1958-12-22 | 1967-02-10 | Ncr Co | Process for forming protective coatings for solid and liquid particles |
FR1351358A (en) | 1958-12-22 | 1964-02-07 | Ncr Co | Process for forming impermeable coatings for particulate matter by liquid phase separation |
NL129921C (en) * | 1958-12-31 | |||
US3170802A (en) * | 1960-12-14 | 1965-02-23 | Zh Noda Sangyo Kagaku Kenkyush | Method for treatment of soybean proteins |
GB1075952A (en) | 1962-12-31 | 1967-07-19 | Gelatine And Glue Res Ass | Microscopic capsules and methods of making them |
US3748277A (en) * | 1965-10-14 | 1973-07-24 | Ncr Co | Process of forming minute capsules |
US3474777A (en) * | 1966-02-10 | 1969-10-28 | Amp Inc | Method of administering therapeutic agents |
US3576758A (en) * | 1966-10-17 | 1971-04-27 | Ncr Co | Treatment of polypeptide-containing hydrophilic polymeric capsule wall material with uranium and vanadium compounds |
FR7981M (en) * | 1967-10-21 | 1970-06-08 | ||
US3491093A (en) * | 1967-11-29 | 1970-01-20 | Endo Lab | Derivatives of 5 aminomethyl-4,5,6,7-tetrahydro-4-oxoindoles |
US3565559A (en) * | 1968-03-11 | 1971-02-23 | Sumitomo Chemical Co | Process for making microcapsules |
US3574832A (en) * | 1968-05-29 | 1971-04-13 | American Cyanamid Co | Therapeutic heparin-surfactant compositions |
GB1236885A (en) | 1968-09-28 | 1971-06-23 | Fuji Photo Film Co Ltd | Method of making multi-wall capsules |
US3567650A (en) * | 1969-02-14 | 1971-03-02 | Ncr Co | Method of making microscopic capsules |
US3937668A (en) * | 1970-07-15 | 1976-02-10 | Ilse Zolle | Method for incorporating substances into protein microspheres |
US3725113A (en) * | 1970-12-17 | 1973-04-03 | Research Corp | Blood compatible microencapsulated detoxicants and method for making |
US3822348A (en) * | 1970-12-28 | 1974-07-02 | Toyo Jozo Kk | Hormone-like substance having serum calcium reducing property |
US3962416A (en) * | 1971-01-25 | 1976-06-08 | Sol Katzen | Preserved nutrients and products |
IL36670A (en) * | 1971-04-21 | 1974-09-10 | Sela M | Therapeutic basic copolymers of amino acids |
US3794561A (en) * | 1971-09-30 | 1974-02-26 | Sasaki T | Biologically active peptide and method of preparing the same |
US3816404A (en) * | 1971-12-08 | 1974-06-11 | Texaco Inc | Preparation of caprolactam |
US3933873A (en) * | 1971-12-08 | 1976-01-20 | Texaco Inc. | Preparation of omega-aminoalkanoic acids |
US3795739A (en) * | 1972-02-14 | 1974-03-05 | Hoffmann La Roche | Treatment of parkinson disease |
JPS5210427B2 (en) * | 1972-07-19 | 1977-03-24 | ||
CA1045977A (en) | 1973-05-17 | 1979-01-09 | Arthur D. Little | Biodegradable, implantable drug delivery device, and process for preparing and using the same |
US4450150A (en) * | 1973-05-17 | 1984-05-22 | Arthur D. Little, Inc. | Biodegradable, implantable drug delivery depots, and method for preparing and using the same |
US4351337A (en) * | 1973-05-17 | 1982-09-28 | Arthur D. Little, Inc. | Biodegradable, implantable drug delivery device, and process for preparing and using the same |
DE2343037A1 (en) | 1973-08-25 | 1975-03-06 | Hoechst Ag | MEDICINAL PRODUCTS WITH ANTIDEPRESSIVE EFFECT |
US3939253A (en) * | 1973-11-02 | 1976-02-17 | Interx Research Corporation | Novel, transient pro-drug forms of l-dopa useful in the treatment of parkinson's disease |
GB1459488A (en) * | 1974-03-19 | 1976-12-22 | Wyeth John & Brother Ltd | Piperazinedione derivatives |
US4061466A (en) * | 1974-10-16 | 1977-12-06 | Ingvar Gosta Holger Sjoholm | Biologically active composition and the use thereof |
US4183849A (en) * | 1975-01-15 | 1980-01-15 | Nordisk Insulinlaboratorium | Therapeutic insulin preparation and a process for the production of a stable insulin preparation with protracted effect |
DK140801B (en) | 1975-01-15 | 1979-11-19 | Nordisk Insulinlab | Process for the preparation of a stable long-acting insulin preparation. |
US4048268A (en) * | 1975-02-19 | 1977-09-13 | Eli Lilly And Company | Stabilization method |
MX3855E (en) | 1975-03-21 | 1981-08-20 | Western Electric Co | IMPROVEMENTS IN THE METHOD FOR MANUFACTURING TRANSISTOR STRUCTURES |
US4035507A (en) * | 1975-04-17 | 1977-07-12 | Interx Research Corporation | Novel, transient pro-drug forms of L-DOPA to treat Parkinson's disease |
DE2517229A1 (en) * | 1975-04-18 | 1976-10-28 | Boehringer Mannheim Gmbh | PHENYLALKYLCARBONIC ACID DERIVATIVES AND PROCESS FOR THEIR PRODUCTION |
CA1077842A (en) | 1975-10-09 | 1980-05-20 | Minnesota Mining And Manufacturing Company | Albumin medicament carrier system |
DE2549999A1 (en) | 1975-11-07 | 1977-05-12 | Boehringer Mannheim Gmbh | PIPERIDINE DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION |
US4405598A (en) * | 1976-01-30 | 1983-09-20 | Fisons, Limited | Composition for treating asthma |
US4117801A (en) * | 1976-06-10 | 1978-10-03 | Eastman Kodak Company | Apparatus for spray coating discrete particles |
FR2374910A1 (en) * | 1976-10-23 | 1978-07-21 | Choay Sa | PREPARATION BASED ON HEPARIN, INCLUDING LIPOSOMES, PROCESS FOR OBTAINING IT AND MEDICINAL PRODUCTS CONTAINING SUCH PREPARATIONS |
US4357259A (en) | 1977-08-01 | 1982-11-02 | Northwestern University | Method of incorporating water-soluble heat-sensitive therapeutic agents in albumin microspheres |
US4217370A (en) * | 1977-08-25 | 1980-08-12 | Blue Wing Corporation | Lipid-containing feed supplements and foodstuffs |
US4199561A (en) * | 1979-02-26 | 1980-04-22 | The Dow Chemical Company | Coated nutrients and medicaments for veterinary use |
US4352883A (en) * | 1979-03-28 | 1982-10-05 | Damon Corporation | Encapsulation of biological material |
US4345588A (en) * | 1979-04-23 | 1982-08-24 | Northwestern University | Method of delivering a therapeutic agent to a target capillary bed |
US4239635A (en) * | 1979-06-11 | 1980-12-16 | Cincinnati Milacron Inc. | Novel diamide and lubricants containing same |
US4272506A (en) * | 1979-08-31 | 1981-06-09 | Syva Company | Purification of reagents by disulfide immobilization |
HU181009B (en) * | 1980-01-18 | 1983-05-30 | Richter Gedeon Vegyeszet | Process for preparing angiotensin-ii analogues with antagonictic activity containing in position 1 sarcosyl,hydroxyacetyl or l-alpha-aminoxy-propionyl group and in positiona 8 esteric group |
NZ196349A (en) | 1980-03-07 | 1984-08-24 | Interx Research Corp | Enhancement of absorption rate of orally administered polar bioactive agents |
IT1148784B (en) * | 1980-04-09 | 1986-12-03 | Eurand Spa | PROCEDURE FOR THE PREPARATION OF MICRO CAPSULES IN A LIQUID VEHICLE |
DE3016170A1 (en) * | 1980-04-26 | 1981-10-29 | Bayer Ag, 5090 Leverkusen | MICROCAPSULES WITH A DEFINED OPENING TEMPERATURE, METHOD FOR THE PRODUCTION AND USE THEREOF |
CA1155853A (en) * | 1980-06-06 | 1983-10-25 | Joseph A. Martin | Imidazole derivatives and preparation thereof |
US4289759A (en) * | 1980-06-23 | 1981-09-15 | Ortho Pharmaceutical Corporation | Immunoregulatory diketopiperazine compounds |
US4348384A (en) * | 1980-10-17 | 1982-09-07 | Dainippon Pharmaceutical Co., Ltd. | Pharmaceutical composition for oral administration containing coagulation factor VIII or IX |
US4442090A (en) * | 1980-11-09 | 1984-04-10 | Kyoto Yakuhin Kogyo Kabushiki Kaisha | Absorption-promoting compounds, compositions thereof with pharmaceuticals and/or bases for rectal administration and method of use |
US4900730A (en) * | 1981-01-14 | 1990-02-13 | Toyo Jozo Co., Ltd. | Preparation which promotes the absorption of peptides |
GB2092136B (en) * | 1981-01-17 | 1985-06-05 | Mitsui Toatsu Chemicals | Production of n-substituted amide compounds |
US4483807A (en) | 1981-01-27 | 1984-11-20 | Japan Atomic Energy Research Institute | Process for producing a slow release composite |
JPS58140026A (en) * | 1982-01-14 | 1983-08-19 | Toyo Jozo Co Ltd | Pharmaceutical having improved absorbability |
FR2509175B1 (en) | 1981-03-06 | 1987-01-16 | Toyo Jozo Kk | THERAPEUTIC PREPARATION HAVING EXCELLENT ABSORPTION PROPERTIES |
NZ201010A (en) | 1981-06-19 | 1986-02-21 | Ciba Geigy Ag | The treatment of inflammation diseases using desferrioxamine |
US4352993A (en) * | 1981-09-09 | 1982-10-05 | Silent Running Corporation | Multiple position power switch |
US4446138A (en) * | 1982-02-10 | 1984-05-01 | Pack Howard M | Method and composition for reducing weight |
CA1241646A (en) * | 1982-02-22 | 1988-09-06 | Adolfo J. De Bold | Atrial natriuretic factor |
US4457907A (en) * | 1982-08-05 | 1984-07-03 | Clear Lake Development Group | Composition and method for protecting a therapeutic drug |
CA1262238A (en) | 1982-09-30 | 1989-10-10 | Richard Insel | Human monoclonal antibodies against bacterial toxins |
US4518433A (en) * | 1982-11-08 | 1985-05-21 | Fmc Corporation | Enteric coating for pharmaceutical dosage forms |
US4393192A (en) * | 1982-12-21 | 1983-07-12 | The Standard Oil Company | Crystalline copolymers prepared from N,N'-terephthaloyldi-beta-alanine and a glycol |
US4473620A (en) * | 1982-12-23 | 1984-09-25 | Eastman Kodak Company | Encapsulated butylated hydroxyanisole |
US4886663A (en) * | 1983-01-03 | 1989-12-12 | Scripps Clinic And Research Foundation | Synthetic heat-stable enterotoxin polypeptide of Escherichia coli and multimers thereof |
JPS59163313A (en) * | 1983-03-09 | 1984-09-14 | Teijin Ltd | Peptide hormone composition for nasal administration |
CA1196862A (en) * | 1983-06-01 | 1985-11-19 | Anthony M.F. Sun | Microencapsulation of living tissue and cells |
CA1196863A (en) * | 1983-06-08 | 1985-11-19 | Mattheus F.A. Goosen | Slow release injectable insulin composition |
US4462839A (en) * | 1983-06-16 | 1984-07-31 | Fmc Corporation | Enteric coating for pharmaceutical dosage forms |
ATE29392T1 (en) | 1983-06-22 | 1987-09-15 | Univ Ohio State Res Found | PREPARATION OF A FINE PARTICULATED MATERIAL AND ENCAPSULATION. |
US4608278A (en) * | 1983-06-22 | 1986-08-26 | The Ohio State University Research Foundation | Small particule formation and encapsulation |
US4692433A (en) * | 1983-10-12 | 1987-09-08 | The Regents Of The University Of California | Method and composition for regulating serum calcium levels of mammals |
JPS60125245A (en) * | 1983-12-12 | 1985-07-04 | Nitto Electric Ind Co Ltd | Preparation of microcapsule containing liquid active substance |
US4671954A (en) * | 1983-12-13 | 1987-06-09 | University Of Florida | Microspheres for incorporation of therapeutic substances and methods of preparation thereof |
US4590265A (en) * | 1984-02-17 | 1986-05-20 | Eastman Kodak Company | Carboxylated cellulose ester and manufacture thereof |
JPS60176549A (en) * | 1984-02-22 | 1985-09-10 | Nisshin Oil Mills Ltd:The | Preparation of protein hydrolyzate |
IL71258A (en) | 1984-03-16 | 1987-12-20 | Yissum Res Dev Co | Pyroglutamic acid derivatives,their preparation and cosmetic preparations comprising them |
US4703042A (en) * | 1984-05-21 | 1987-10-27 | Bodor Nicholas S | Orally active heparin salts containing multivalent cationic units |
FR2565102B1 (en) * | 1984-06-05 | 1987-03-20 | Paris Sud Universite | BIODEGRADABLE MICROCAPSULES BASED ON SERUMALBUMIN, THEIR PREPARATION AND THEIR APPLICATION TO THE IN SITU RELEASE OF MEDICUMENTS |
US4757066A (en) * | 1984-10-15 | 1988-07-12 | Sankyo Company Limited | Composition containing a penem or carbapenem antibiotic and the use of the same |
IT1177384B (en) * | 1984-12-12 | 1987-08-26 | Boeehringer Biochemia Robin Sp | DIETARY GRANULAR PRODUCTS BASED ON AMINO ACIDS AND PROCEDURE FOR THEIR PREPARATION |
US4708952A (en) * | 1985-02-06 | 1987-11-24 | Aida Salatinjants | Method of treatment of the infectious and viral diseases by one time interference |
CS254355B1 (en) * | 1985-04-10 | 1988-01-15 | Vladimir Saudek | Soluble and biodegradatable copolymeres activated for bond of biologicaly active substances |
US4908233A (en) * | 1985-05-08 | 1990-03-13 | Lion Corporation | Production of microcapsules by simple coacervation |
US4757024A (en) * | 1985-05-31 | 1988-07-12 | Biostar Medical Products, Inc. | Immune complex detection method and article using immunologically non-specific immunoglobulins |
US4897444A (en) * | 1985-05-31 | 1990-01-30 | The Research Foundation Of The State University Of New York | Immobilized fluorogenic substrates for enzymes; and processes for their preparation |
US4683092A (en) * | 1985-07-03 | 1987-07-28 | Damon Biotech, Inc. | Capsule loading technique |
US4789734A (en) * | 1985-08-06 | 1988-12-06 | La Jolla Cancer Research Foundation | Vitronectin specific cell receptor derived from mammalian mesenchymal tissue |
IT1214629B (en) * | 1985-08-29 | 1990-01-18 | Formenti Farmaceutici Spa | MICRO-ENCAPSULATION PROCEDURE OF A MEDICATION, MEDICATION SO PREPARED, AND PHARMACEUTICAL COMPOSITIONS THAT INCLUDE IT |
DE3682257D1 (en) * | 1985-11-22 | 1991-12-05 | Takeda Chemical Industries Ltd | LIPOSOME COMPOSITION. |
LU86258A1 (en) | 1986-01-21 | 1987-09-03 | Rech Dermatologiques C I R D S | BENZAMIDO AROMATIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THEIR USE IN HUMAN OR VETERINARY MEDICINE AND IN COSMETICS |
IT1188550B (en) * | 1986-02-07 | 1988-01-14 | Sclavo Spa | SYNTHETIC PEPTIDE WITH INTERLEUKINA 1 HUMAN ACTIVITY |
US4919939A (en) * | 1986-04-29 | 1990-04-24 | Pharmetrix Corporation | Periodontal disease treatment system |
US4692284A (en) * | 1986-04-30 | 1987-09-08 | Damon Biotech, Inc. | Method and apparatus for forming droplets and microcapsules |
DE3618944A1 (en) * | 1986-06-05 | 1987-12-10 | Henkel Kgaa | QUARTAERE 2-ALKYLIMIDAZOLINIAL SALTS, METHOD FOR THE PRODUCTION AND USE THEREOF |
US4837381A (en) * | 1986-08-11 | 1989-06-06 | American Cyanamid Company | Compositions for parenteral administration and their use |
NZ221411A (en) * | 1986-08-11 | 1989-10-27 | Innovata Biomed Ltd | Pharmaceutical compositions containing microcapsules and a surfactant |
AU610083B2 (en) * | 1986-08-18 | 1991-05-16 | Clinical Technologies Associates, Inc. | Delivery systems for pharmacological agents |
CH668257A5 (en) | 1986-09-23 | 1988-12-15 | Moeller Willi Fa | DICARBONIC ACID DIAMOND, THESE CONTAINING ION SELECTIVE MEMBRANES AND TEST DEVICES, AND LITHIUM COMPLEXES OF DICARBONIC ACID DIAMOND. |
DE3700128A1 (en) | 1987-01-03 | 1988-07-14 | Hoechst Ag | BIODEGRADABLE POLY- (HYDROXYALKYL) - AMINODICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION AND USE THEREOF FOR DEPOT PREPARATIONS WITH CONTROLLED ACTIVE SUBSTANCE DELIVERY |
US5077278A (en) * | 1987-01-23 | 1991-12-31 | Pfizer Inc. | Non-natural demethylavermectins compositions and method of use |
US5069936A (en) * | 1987-06-25 | 1991-12-03 | Yen Richard C K | Manufacturing protein microspheres |
JPH0725725B2 (en) * | 1987-07-23 | 1995-03-22 | 保土谷化学工業株式会社 | Benzamide derivative |
MX12394A (en) * | 1987-07-23 | 1993-12-01 | Ciba Geigy Ag | PROCEDURE FOR OBTAINING POLYETHYLENE GLYCOL CARBAMATES. |
US4895725A (en) * | 1987-08-24 | 1990-01-23 | Clinical Technologies Associates, Inc. | Microencapsulation of fish oil |
US5067961A (en) | 1988-02-18 | 1991-11-26 | Autogenesis Technologies, Inc. | Non-biodegradable two phase corneal implant and method for preparing same |
JP2670680B2 (en) * | 1988-02-24 | 1997-10-29 | 株式会社ビーエムジー | Polylactic acid microspheres containing physiologically active substance and method for producing the same |
GB8811409D0 (en) | 1988-05-13 | 1988-06-15 | Unilever Plc | Cosmetic composition |
GB8811408D0 (en) | 1988-05-13 | 1988-06-15 | Unilever Plc | Cosmetic composition |
US5055300A (en) * | 1988-06-17 | 1991-10-08 | Basic Bio Systems, Inc. | Time release protein |
US5271923A (en) | 1988-07-05 | 1993-12-21 | Manac Incorporated | Solid radiographic contrast medium |
FR2636238B1 (en) * | 1988-09-14 | 1994-01-21 | Morelle Jean | NEW ANTISUDORAL COMPOSITIONS |
GB8822857D0 (en) | 1988-09-29 | 1988-11-02 | Patralan Ltd | Pharmaceutical formulations |
GB8823731D0 (en) | 1988-10-10 | 1988-11-16 | Smith Kline French Lab | Biologically active compounds |
US5039481A (en) * | 1988-12-16 | 1991-08-13 | Clean Air, Inc. | Aliphatic polycarboxylic acids as air purification compositions |
US4976968A (en) * | 1989-02-24 | 1990-12-11 | Clinical Technologies Associates, Inc. | Anhydrous delivery systems for pharmacological agents |
US4983402A (en) * | 1989-02-24 | 1991-01-08 | Clinical Technologies Associates, Inc. | Orally administerable ANF |
CA2012306A1 (en) | 1989-03-28 | 1990-09-28 | Werner Neidhart | Amino acid derivatives |
US5122367A (en) | 1989-03-31 | 1992-06-16 | Massachusetts Institute Of Technology | Polyanhydride bioerodible controlled release implants for administration of stabilized growth hormone |
US4963364A (en) * | 1989-04-10 | 1990-10-16 | Fox Sidney W | Microencapsulated antitumor agent |
US5019400A (en) | 1989-05-01 | 1991-05-28 | Enzytech, Inc. | Very low temperature casting of controlled release microspheres |
US5100918A (en) | 1989-05-25 | 1992-03-31 | Sterling Drug, Inc. | Prevention or treatment of sunburn using the S(+) isomer of ibuprofen |
US4996292A (en) * | 1989-06-30 | 1991-02-26 | Fox Sidney W | Self-sealing artificial skin comprising copoly-alpha-amino acid |
JP2911496B2 (en) | 1989-09-11 | 1999-06-23 | 帝國製薬株式会社 | Highly absorbable vaginal agent containing bioactive polypeptide |
US5271961A (en) * | 1989-11-06 | 1993-12-21 | Alkermes Controlled Therapeutics, Inc. | Method for producing protein microspheres |
US5216124A (en) | 1989-12-15 | 1993-06-01 | G. D. Searle & Co. | Substituted cyclic tetrapeptides |
US5389377A (en) | 1989-12-22 | 1995-02-14 | Molecular Bioquest, Inc. | Solid care therapeutic compositions and methods for making same |
US5126147A (en) | 1990-02-08 | 1992-06-30 | Biosearch, Inc. | Sustained release dosage form |
FR2658076B1 (en) | 1990-02-12 | 1992-06-12 | Sanofi Sa | COSMETIC COMPOSITION CONTAINING COPOLYMERS OF AMINO ACIDS, USEFUL AS A MOISTURIZING AGENT. |
JPH05268986A (en) | 1990-03-19 | 1993-10-19 | Bristol Myers Squibb Co | Monoclonal antibody and activation of lymphocyte |
GB9007052D0 (en) | 1990-03-29 | 1990-05-30 | Skua Investments Ltd | Pharmaceutical formulations |
JP3249147B2 (en) | 1990-06-01 | 2002-01-21 | キリン−アムジエン・インコーポレーテツド | Oral preparation containing bioactive protein |
CA2046830C (en) | 1990-07-19 | 1999-12-14 | Patrick P. Deluca | Drug delivery system involving inter-action between protein or polypeptide and hydrophobic biodegradable polymer |
US5714167A (en) | 1992-06-15 | 1998-02-03 | Emisphere Technologies, Inc. | Active agent transport systems |
US5541155A (en) | 1994-04-22 | 1996-07-30 | Emisphere Technologies, Inc. | Acids and acid salts and their use in delivery systems |
US5451410A (en) | 1993-04-22 | 1995-09-19 | Emisphere Technologies, Inc. | Modified amino acids for encapsulating active agents |
US5447728A (en) | 1992-06-15 | 1995-09-05 | Emisphere Technologies, Inc. | Desferrioxamine oral delivery system |
US5578323A (en) | 1992-06-15 | 1996-11-26 | Emisphere Technologies, Inc. | Proteinoid carriers and methods for preparation and use thereof |
US5693338A (en) | 1994-09-29 | 1997-12-02 | Emisphere Technologies, Inc. | Diketopiperazine-based delivery systems |
US5443841A (en) | 1992-06-15 | 1995-08-22 | Emisphere Technologies, Inc. | Proteinoid microspheres and methods for preparation and use thereof |
US5629020A (en) | 1994-04-22 | 1997-05-13 | Emisphere Technologies, Inc. | Modified amino acids for drug delivery |
JPH05239021A (en) * | 1990-09-04 | 1993-09-17 | Microbial Chem Res Found | New actinonin derivative |
US5418010A (en) * | 1990-10-05 | 1995-05-23 | Griffith Laboratories Worldwide, Inc. | Microencapsulation process |
DE4033419A1 (en) * | 1990-10-20 | 1992-04-23 | Wolman Gmbh Dr | POLYMOUS NITROGEN COMPOUNDS AND METAL FIXING SAEURS CONTAINING WOOD PROTECTION AGENTS |
US5271934A (en) | 1990-10-22 | 1993-12-21 | Revlon Consumer Products Corporation | Encapsulated antiperspirant salts and deodorant/antiperspirants |
JP3179538B2 (en) | 1990-12-11 | 2001-06-25 | ノバルティス アクチエンゲゼルシャフト | Aqueous solution of stable human calcitonin |
US5137892A (en) | 1990-12-12 | 1992-08-11 | Abbott Laboratories | Quinoline, naphthyridine and pyridobenzoxazine derivatives |
US5244653A (en) | 1991-05-01 | 1993-09-14 | Isp Chemicals Inc. | Glycine anhydride dimethylol as a biocide and preservative |
CA2070061C (en) | 1991-06-07 | 2004-02-10 | Shigeyuki Takama | Physiologically active polypeptide-containing pharmaceutical composition |
US5250236A (en) * | 1991-08-05 | 1993-10-05 | Gasco Maria R | Method for producing solid lipid microspheres having a narrow size distribution |
ZA93929B (en) | 1992-02-18 | 1993-09-10 | Akzo Nv | A process for the preparation of biologically active materialcontaining polymeric microcapsules. |
US5352461A (en) | 1992-03-11 | 1994-10-04 | Pharmaceutical Discovery Corporation | Self assembling diketopiperazine drug delivery system |
US5310535A (en) | 1992-04-24 | 1994-05-10 | The Dow Chemical Company | Carboxamide modified polyamine chelators and radioactive complexes thereof for conjugation to antibodies |
HU211995B (en) | 1992-06-30 | 1996-01-29 | Gyogyszerkutato Intezet | Process to prepare novel benzoyl amino acid derivs. and pharmaceutical compns. contg.them |
PH30929A (en) * | 1992-09-03 | 1997-12-23 | Janssen Pharmaceutica Nv | Beads having a core coated with an antifungal and a polymer. |
US5401516A (en) | 1992-12-21 | 1995-03-28 | Emisphere Technologies, Inc. | Modified hydrolyzed vegetable protein microspheres and methods for preparation and use thereof |
AU6096094A (en) * | 1993-01-27 | 1994-08-15 | Georgetown University | Method and composition employing (2r,4s) itraconazole |
IT1263831B (en) * | 1993-01-29 | 1996-09-04 | Paolo Chiesi | MULTI-COMPONENT INCLUSION COMPLEXES WITH HIGH SOLUBILITY CONSTITUTED BY A BASIC-TYPE DRUG, AN ACID AND A CYCLODEXTRINE |
US5439686A (en) | 1993-02-22 | 1995-08-08 | Vivorx Pharmaceuticals, Inc. | Methods for in vivo delivery of substantially water insoluble pharmacologically active agents and compositions useful therefor |
DK0616799T3 (en) | 1993-03-24 | 2000-09-18 | Collaborative Lab Inc | Cosmetic application system for salicylic acid and process for their preparation |
US5709861A (en) | 1993-04-22 | 1998-01-20 | Emisphere Technologies, Inc. | Compositions for the delivery of antigens |
US5643957A (en) | 1993-04-22 | 1997-07-01 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
ATE171715T1 (en) * | 1993-04-23 | 1998-10-15 | Rhodia Chimie Sa | POLYANHYDROASPARAGIC ACID AND ITS BIODEGRADABLE HYDROLYSIS PRODUCTS |
US5530137A (en) | 1994-09-16 | 1996-06-25 | Betz Paperchem, Inc. | Methods and compositions for stabilizing fatty acid imidazoline solutions |
US5650386A (en) | 1995-03-31 | 1997-07-22 | Emisphere Technologies, Inc. | Compositions for oral delivery of active agents |
US5750147A (en) | 1995-06-07 | 1998-05-12 | Emisphere Technologies, Inc. | Method of solubilizing and encapsulating itraconazole |
US6051258A (en) * | 1995-06-07 | 2000-04-18 | Emisphere Technologies, Inc. | Proteinoid emulsions and methods for preparation and use thereof |
US5667806A (en) | 1995-06-07 | 1997-09-16 | Emisphere Technologies, Inc. | Spray drying method and apparatus |
-
1995
- 1995-06-07 US US08/475,887 patent/US5750147A/en not_active Expired - Lifetime
-
1996
- 1996-06-06 EP EP96919396A patent/EP0831703A4/en not_active Withdrawn
- 1996-06-06 WO PCT/US1996/010222 patent/WO1996039835A1/en not_active Application Discontinuation
- 1996-06-06 AU AU61747/96A patent/AU6174796A/en not_active Abandoned
-
1997
- 1997-11-11 US US08/967,486 patent/US6100285A/en not_active Expired - Lifetime
-
2000
- 2000-01-06 US US09/478,661 patent/US6461545B1/en not_active Expired - Lifetime
-
2002
- 2002-08-15 US US10/222,640 patent/US20030042638A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
US6100285A (en) | 2000-08-08 |
WO1996039835A1 (en) | 1996-12-19 |
US5750147A (en) | 1998-05-12 |
EP0831703A1 (en) | 1998-04-01 |
US6461545B1 (en) | 2002-10-08 |
EP0831703A4 (en) | 2003-05-21 |
AU6174796A (en) | 1996-12-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6461545B1 (en) | Method of solubilizing and encapsulating itraconazole | |
US5667806A (en) | Spray drying method and apparatus | |
US8133514B2 (en) | Carbon-substituted diketopiperazine delivery systems | |
EP1025840B1 (en) | Oral drug compositions | |
US6180140B1 (en) | Modified amino acids for drug delivery | |
US5447728A (en) | Desferrioxamine oral delivery system | |
US6461643B2 (en) | Oral drug delivery compositions and methods | |
EP1631308B1 (en) | Novel methods and compositions for enhanced transmucosal delivery of peptides and proteins | |
US5811127A (en) | Desferrioxamine oral delivery system | |
US5976569A (en) | Diketopiperazine-based delivery systems | |
CA2012791C (en) | Spray gel base and spray gel preparation | |
US5820881A (en) | Microspheres of diamide-dicarboxylic acids | |
US5792451A (en) | Oral drug delivery compositions and methods | |
US5541155A (en) | Acids and acid salts and their use in delivery systems | |
WO1996010396A9 (en) | Carbon-substituted diketopiperazine delivery systems | |
JP2001517694A (en) | Activator delivery system | |
CA2375914A1 (en) | Formulations comprising dehydrated particles of pharmaceutical agents and process for preparing the same | |
AU2004255458B2 (en) | Orally dosed pharmaceutical compositions comprising a delivery agent in micronized form | |
IE920516A1 (en) | Steroid Formulations | |
US20220183989A1 (en) | A delivery system comprising silicon-containing material | |
CA2518102C (en) | Powdery preparation for nasal administration | |
WO2004113332A1 (en) | Nasal preparations |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |