|Publication number||USRE28819 E|
|Application number||US 05/568,631|
|Publication date||May 18, 1976|
|Filing date||Apr 16, 1975|
|Priority date||Dec 8, 1972|
|Publication number||05568631, 568631, US RE28819 E, US RE28819E, US-E-RE28819, USRE28819 E, USRE28819E|
|Inventors||Geoffrey F. Thompson|
|Original Assignee||Syntex (U.S.A.) Inc.|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (3), Non-Patent Citations (4), Referenced by (167), Classifications (10)|
|External Links: USPTO, USPTO Assignment, Espacenet|
This invention relates to medicament preparations and vehicles therefor. In presently preferred embodiments, the present invention relates to medicament preparations wherein the chemical potency of the medicament is stabilized, for extended periods of time, by dispersing or dissolving the medicament in an antioxidant containing dialkylated mono- or poly-alkylene glycol vehicle therefor.
The use of alkylene glycols or monoalkyl ethers thereof, either alone or in combination with other vehicle components as carriers for medicaments, such as steroids or prostaglandins, is well-known. See, for example, Great Britain Pat. No. 1,133,800; South African Pat. No. 70/04245; and U.S. Pat. Nos. 2,600,344; 2,856,329; 3,069,322; 3,592,930; and 3,673,213. Such carriers, however, do not, in general, provide requisite stabilizing properties for the medicament material. That is, after relatively short storage times, the chemical potency of the active medicament has degraded significantly to a point where the preparation, if taken at the recommended dosage level, might be of insufficient activity to accomplish the desired therapeutic objective.
Of particular interest in the present invention are the family of materials known as prostaglandins. Prostaglandins are a group of chemically related 20-carbon chain hydroxy ffatty acids having the basic skeleton of prostanoic acids: ##SPC1##
The prostaglandins having a hydroxy group at the C-11 position and a keto group at the C-9 position are known as the PGE series. Those having a hydroxyl group in place of the keto group at the C-9 position are known as the PGF series and are further designated by an α or β suffix to indicate the configuration of the hydroxyl group at the C-9 position. The natural compounds are the α-hydroxy substituted compounds. They may contain different degrees of unsaturation in the molecule, particularly at C-5, C-13, and C-17, the unsaturation is also indicated by a suffix. Thus, for example, PGE1 refers to a prostanoic acid having a trans olefin bond at the 13-position. For a review on prostaglandins and the definition of primary prostaglandins, see, for example, S. Bergstrom, Recent Progress in Hormone Research 22, pp. 153-175 (1966) and S. Bergstrom, Science 157, page 382 (1967).
Using accepted nomenclature, prostaglandins of the PGE, PGF, PGA and PGB series are named as follows:
Pge1 : 11α,15α-dihydroxy-9-keto-13-prostenoic acid;
Pge2 : 11α,15α-dihydroxy-9-keto-5,13-prostadienoic acid;
Pge3 : 11α,15α-dihydroxy-9-keto-5,13-17-prostatrienoic acid;
Pgf1 : 9α,11α,15α-trihydroxy-13-prostenoic acid;
Pgf2 : 9α,11α,15α-trihydroxy-5,13-prostadienoic acid;
Pga1 : 15α-hydroxy-9-keto-10,15-prostadienoic acid;
Pga2 : 15α-hydroxy-9-keto-10,13,17-prostatrienoic acid;
Pgb1 : 15α-hydroxy-9-keto-8,13-prostadienoic acid; and,
Pgb2 : 15α-hydroxy-9-keto-10,13,17-prostatrienoic acid.
Prostaglandins are widely distributed in mammalian tissues and have been isolated from natural sources in very small amounts. In addition a number of the natural occurring prostaglandins have been prepared by chemical synthesis; see for example, J. Am. Chem. Soc. 91, 5675 (1969), J. Am. Chem. Soc. 92, 2586 (1970), J. Am. Chem. Soc. 93, 1489-1493 (1971) and references cited therein, W. P. Schneider et al, J. Am. Chem Soc. 90, 5895 (1968), U. Axen et al, Chem. Commun., 303 (1969), and W. P. Schneider, Chem. Commun. 304 (1969).
Because of the remarkable range of biological and pharmacological properties exhibited by this family of compounds, a great deal of interest has focused upon such compounds. It is known, however, that prostaglandins in general, and specifically PGE2, are, from a chemical point of view, relatively unstable. See, for example, Brummer J. Pharm. Pharmac. 23, 804 (1971), and Karim et al, European J. Pharmacol. 4, 416 (1968). It would, therefore, be desirable to have a prostaglandin preparation wherein the prostaglandin material is stabilized by the vehicle material.
It is the primary object of this invention to provide novel vehicles for medicament preparations.
It is a further object of this invention to provide novel vehicles for medicaments which, in addition to serving as a carrier for the medicament, stabilize for an extended period of time the chemical potency of the medicament.
It is a further object of this invention to provide dialkylated mono- and poly-alkylene glycols as vehicles for medicament preparations.
It is a further object of this invention to provide medicament preparations having a dialkylated mono- or poly-alkylene glycol as the vehicle therefor.
It is a further object of this invention to provide novel, substantially anhydrous pharmaceutical preparations containing a dialkylated mono- or poly-alkylene glycol as the vehicle and at least one prostaglandin material.
It is a further object of this invention to provide medicament preparations having dialkylated mono- or poly-alkylene glycols as the vehicle therefor, and where the chemical potency of the medicament material is stabilized for extended periods of time through use of such dialkylated glycol vehicle.
It is a further object of this invention to provide substantially anhydrous prostaglandin preparations wherein the chemical potency of the prostaglandin material is stabilized through use of a dialkylated mono- or poly-alkylene glycol as the vehicle for the preparation.
It is a further object of the present invention to provide a substantially anhydrous aspirin preparation where the chemical potency of the aspirin is stabilized through use of a dialkylated mono- or poly-alkylene glycol vehicle.
It is a further object of this invention to provide novel, substantially anhydrous pharmaceutical preparations containing a medicament material, a dialkylated mono- or poly-alkylene glycol as a vehicle for the medicament material, and at least one antioxidant for the glycol vehicle.
These and still further objects, features, and advantages of the present invention will become apparent upon consideration of the following detailed disclosure.
The above and still further objects, features, and advantages of the present invention are achieved, in accordance therewith, by admixing a pharmaceutically active quantity of an active medicament material with a quantity of an antioxidant-containing dialkylated mono- or poly-alkylene glycol. In a specific embodiment, for example, the combination of PGE2 with the dimethyl ether of polyethylene glycol 550 has exhibited a high degree of chemical stability after storage for an extended period of time at above room temperature.
The dialkylated mono- or poly-alkylene glycol of the present invention can be represented by the following structural formula: ##EQU1## where R and R1 are lower alkyl, R2 is lower alkyl or hydrogen, m is an integer from 1 to 6, and n is an integer from 1 to a very large number, such as 500, such that the molecular weight of the glycol vehicle can be up to about 20,000 or so.
As used in this specification, the term "lower alkyl" refers to both straight and branched chain alkyl groups having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-amyl, n-hexyl, and the like.
Illustrative dialkylated glycol vehicles include for example, 1,2-dimethoxyethane (i.e., glyme), diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, etc., where the numbers such as 350, 550 and 750, refer to the approximate average molecular weight of the polyethylene glycol vehicle. Depending upon the vehicle utilized and its molecular weight (or average molecular weight), the vehicle, and the corresponding pharmaceutical preparation will be liquids, semi-solids or waxes or solids at room temperature. Thus, as more fully described below, the pharmaceutical preparations of the present invention may take on a variety of unit dosage forms.
The dialkylated mono- or poly-alkylene glycols of the present invention are satisfactory carriers for a wide variety of active medicament materials, as will be shown below, and, in addition, has been shown to stabilize the chemical potency or activity of two distinct medicaments, i.e., PGE2 and aspirin. The dialkylated glycol vehicle, however, is, itself, subject to undesirable oxidation and, therefore, should include a minor amount, generally about 0.01% to about 1.0%, of one or more antioxidants to protect the chemical stability of the vehicle itself. Exemplary antioxidants include propyl gallate, vitamin E, hydroquinone, hydroxycomarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, dithiocarbamates, butylated hydroxyanisole, and butylated hydroxytoluene, with a 50--50 mixture (by weight) of butylated hydroxyanisole and butylated hydroxy toluene presently being preferred.
In addition, the dialkylated glycol vehicle should be as pure as is technically or economically feasible. In particular, it should be substantially devoid of peroxides and/or other oxidation products thereof which tend in the quantities present in the vehicle, to interfere with its vehicle and/or stabilizing properties.
The medicament which can be utilized in the preparations of the present invention include therapeutic agents for topical application including antibiotics such as tetracycline, oxytetracycline, chlortetracycline, chloramiphenicol, gramicidin, and the like; anesthetics such as benzocaine, xylocaine, and the like; analgesics such as aspirin, 2-(6-methoxy-2-naphthyl) propionic acid, and the like; steroids having anti-inflammatory or other beneficial activity, such as 6α,9α-difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-pregna-1,4-diene-3,20-dione, 9α,11β,21-trichloro-6α-fluoro-16α,17α-isopropylidenedioxy-pregna-1,4-diene-3,20-dione, and those described in U.S. 3,592,930 which partial disclosure is incorporated herein by reference, and the like; naturally occurring or synthetic prostaglandins, such as PGE2, PGF2.sub.α, the other prostaglandins referred to above, and the like; N,N-bis-(2-hydroxyethyl)-palmitamide; antihistamines; antibacterials and fungicides; etc.
Incorporation of the medicament into the vehicle is in accordance with standard techniques and practices common to the pharmaceutical field, for example as described in Remington's Practice of Pharmacy, 12th Edition by Martin and Cook, Mach Publishing Company (1961).
The ratio of medicament to the dialkylated glycol vehicle can vary, depending upon the concentration of the medicament desired in the final unit dosage form. In general, however, the preparation should contain a therapeutically effective amount of the medicament, generally about 0.001%-10%, with the balance being substantially the dialkylated glycol vehicle. In formulating the preparation, care should be taken to select a method which substantially eliminates water from the preparation so as to make it substantially anhydrous. Methods which do not substantially eliminate water are not desirable since water retention in the preparation will result in reduced activity or potency of the preparation over an extended period of time. Retention or uptake of a minimum amount of water, up to about 5%, is for all practical purposes, unavoidable and, therefore, not undesirable. It is preferred, however, to maintain the amount of residual water at the lowest practical level and certainly at a level which does not diminish the advantages afforded by the present invention.
As indicated above, the present invention is applicable to the use of a great variety of medicament materials as the pharmaceutically active component of the preparations of the present invention, such as, for example, the naturally occurring or synthetic prostaglandins specifically set forth above. It has been shown that the vehicle of this invention has stabilizing properties with respect to certain medicaments. Certain of such medicaments, including certain prostaglandins, are more stable than other medicaments and, to the extent that they are more stable, the stabilizing effect of the dialkylated glycol vehicle may be correspondingly diminished. The combination of the dialkylated glycol vehicle and a relatively stable medicament is, nonetheless, considered to be within the scope of the present invention. To the extent that the particular medicament is relatively chemically unstable, as for example is PGE2, the dialkylated glycol vehicle has been found to enhance the chemical stability of the medicament during long periods of storage at or above room temperature.
The final preparation should have a pH, or be adjusted to a pH, which provides for optimum stability for a given active component. For example, the pH of a PGE2 formulation should be adjusted to about 4-5 (as determined from a 10% aqueous solution of the formulation) if the formulation is to have extended stability. pH adjustment can be made with any suitable acid or base, for example, citric acid, acetic acid, benzoic acid, hydrochloric acid, phosphoric acid, and the like.
Either at the time of initial production of the preparation of the present invention, or at some time subsequent thereto, the preparation can be formulated into a variety of pharmaceutical or veterinary compositions and, as such, can be administered in a wide variety of dosage forms suitable for enteral, parenteral, or topical administration. Such compositions may have a single medicament as the sole active component or a combination of pharmaceutically compatible medicaments may be utilized. The preparation is, thus, typically administered as a pharmaceutical composition containing the pharmaceutically active medicament(s) and/or a pharmaceutically acceptable salt thereof, the dialkylated glycol vehicle, and one or more non-toxic antioxidants for the glycol vehicle. If desired, additional carrier or adjuvants may be utilized in preparing the pharmaceutical compositions. The administerable pharmaceutical composition may take the form of creams, ointments, oral or vaginal tablets, rectal or vaginal suppositories, encapsulated preparations, bougies, food premixes, of the like, preferably in unit dosage forms for simple administration of precise dosages. Since the vehicles of this invention are generally liquids or semi-solids, depending upon the molecular weight thereof, creams, ointments, suppositories and solutions are the preferred administration forms. Auxiliary non-toxic solid carriers which can be used in conjunction with the dialkylated glycol vehicle for tablet preparations include, for example, pharmaceutical grades of mannitol, lactose, starches, magnesium stearate, sodium saccharin, talcum, sodium bisulfite, and the like. Liquid pharmaceutically administerable compositions can, for example, be formulated by utilizing a liquid dialkylated glycol vehicle to thereby form a solution. If desired, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc. Actual methods or preparing such dosage forms, are known, or will be apparent, to those skilled in this art.
The following specific description is given to enable those skilled in this art to more clearly understand and practice the present invention. It should not be considered as a limitation upon the scope of the invention but merely as being illustrative and representative thereof.
The solubility (expressed as mg. medicament per ml. of vehicle) at 30°C of fourteen different medicaments in polyethylene glycol-550-dimethyl ether is given in the following table:
TABLE I______________________________________ Solubility,Ex. Medicament (mg./ml.)______________________________________I 6α,9α-difluoro-11β-hydroxy-16α,17α-isopropylidenedioxy-pregna-1,4-diene-3,20-dione 6.5II 9α,11β,21-trichloro-6α-fluoro-16α,17α-isopropylidenedioxy-pregna-1,4,-diene-3,20-dione 1.5III PGE.sub.2 2.0IV PGF.sub.2.sub.α 36.0V N,N-bis(2-hydroxyethyl)-palmitamide 2.7VI 2-(6-methoxy-2-naphthyl)propionic acid 50.0VII aspirin (acetylsalicylic acid) 120.0VIII benzocaine 111.0IX xylocaine 57.0X chloramphenicol 70.0XI gramicidin 4.4XII tetracycline 125.0XIII oxytetracycline hydrochloride 0.34XIV chlortetracycline hydrochloride 0.416______________________________________
A formulation is prepared having 0.5 g. aspirin per 1.0g. polyethylene glycol- 750-dimethyl ether, and stored at 80°C. Decomposition of the aspirin is measured vs. time. The time for 10% decomposition is 27 hours. This reflects approximately a 30 month shelf-life at 25°C. This can be compared to a published report [Jun et al, J. Pharm. Sec. Vol. 61,1160(1972)] which indicates that the time for 10% decomposition of aspirin in several polyethylene glycols at 80°C. is 2 hours reflecting a shelf-life at 25°C. of only 3.5 months.
A formulation is prepared having 1 mg. PGE2 per ml. 1,2-dimethoxyethane. After 12 days storage at 60°C. under a nitrogen atmosphere, the PGE2 assays 100% of the activity at time zero.
A formulation is prepared having 1 mg. PGE2 per ml. of triethylene glycol-dimethyl ether. After 5 days storage at 60°C. under a nitrogen atmosphere, the PGE2 assays 100% of the activity at time zero.
The following formulations are prepared having 1 mg. PGE2 per ml. of polyethylene glycol-550-dimethyl ether, and the additional material(s) as set forth below. The percent activity of the PGE2 after storage for 7 days at 80°C. is also given.
______________________________________Example Additional Material(s) Activity______________________________________XVIII 0.05% citric acid, 0.025% BHA, and 99% 0.025% BHT (sealed under air)XIX Same as XVIII, except sealed 91% under nitrogenXX Same as XVIII, except 0.1% citric 82% acidXXI Same as XX, except sealed under 86% nitrogenXXII Same as XVIII 87%XXIII Same as XIX 87%XXIV 0.05% citric acid and 0.05% BHA 81% (sealed under air)XXV Same as XXIV, except sealed under 99% nitrogen______________________________________
A formulation is prepared having 1 mg. PGE2, 0.01% edetic acid, 0.01% BHA and 0.01% BHT per ml. polyethylene glycol-550-dimethyl ether, and sealed in an ampule under nitrogen atmosphere. After 18 days storage at 80°C., the PGE2 assays 100% of the activity at time zero.
The following formulations are prepared having 1 mg. PGE2 per ml. polyethylene glycol-550 -dimethyl ether, and the additional material(s) as set forth below, and the sealed in individual ampules under nitrogen atmosphere. The time (t90) for 10% of the PGE2 to decompose when stored at 80°C. is given. Also given is the corresponding t90 for a formulation having 1 mg. PGE2 per ml. polyethylene glycol-400, also sealed under nitrogen atmosphere.
______________________________________Example Additional Material(s) t.sub.90______________________________________-- (PGE.sub.2 in PEG 400) 20 hoursXXVII 0.1% citric acid 7.1 daysXXVIII 0.01% citric acid 8.8 daysXXIX 0.01% BHA, 0.01% BHT, and undecomposed 0.01% EDTA after 18 days______________________________________
By comparison, 1 mg. PGE2 and 1 ml. polyethylene glycol 400 assays 54% PGE2 activity after storage for two months at 45°C.; 0.2 mg. PGE2 in 2.7598 g. polyethylene glycol 4,000 assays 70% PGE2 activity after storage for 6 months at room temperature and 72% PGE2 activity after storage for 3 months at 45°C.; a suppository of 0.2 mg. PGE2 in 2.7298 g. base comprising 2% polyethylene glycol 4,000 and 98% polyethylene glycol 1,000 assays 62% PGE2 activity after storage for six months at room temperature; a formulation of PGE2 in polyethylene glycol 400 assays 73% PGE2 activity after 4 months at room temperature; and a formulation of PGE2 in polyethylene glycol 4000 assays 82% PGE2 activity after 5 months at room temperature.
It can thus be seen (from Examples XV-XXIX hereof) that the incorporation of aspirin or a prostaglandin material, particularly PGE2, into the dialkylated glycol vehicle of the present invention stabilizes, for extended periods of time, the chemical potency of the particular medicament.
For a discussion of the significance of the date presented herein, and the extrapolation thereof to shelf-lives at room temperature, reference should be made, for example, to Kennon, "Use of Models in Determining Chemical Pharmaceutical Stability," J. of Pharm. Sciences, 53, 815-818 (July, 1964).
A formulation is prepared containing 1 mg. PGE2 per ml. of the diethyl ether of polyethylene glycol-750, and 0.025% BHA and 0.025% BHT.
A formulation is prepared having 1 mg. PGE2 per ml. of the dipropylether of polyethylene glycol-550, and 0.025% BHA and 0.025% BHT.
A formulation is prepared having 1 mg. PGE2 per ml. of the dimethyl ether of propylene glycol, and 0.025% BHA and 0.025% BHT.
A formulation is prepared having 2 mg. of N,N-bis(2-hydroxyethyl)-oleamide per ml. of 1,2-dimethoxyethane containing 0.025% BHT and 0.025% BHA. After 5 weeks at 80°C, the oleamide assays 96% of the activity at time zero. This reflects approximately 3-4 years shelf time at 25°C. In vitro, this compound inhibits lipase and, thus, may have utility as an anti-acne preparation.
While the present invention has been described with reference to specific embodiments thereof, it should be understood by those skilled in this art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material or composition of matter, process, process step or steps, or then-present objective to the spirit of this invention without departing from its essential teachings.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US3308217 *||Feb 9, 1965||Mar 7, 1967||Lowy Lawrence||Method of granulating materials for subsequent forming into tablets|
|US3629111 *||Oct 2, 1970||Dec 21, 1971||Olin Corp||Hydraulic fluids containing novel inhibitor compositions|
|FR1296515A||Title not available|
|1||Agami, Chem. Abst., vol. 69 (1968) p. 76074X.|
|2||*||Agami, Chem. Abst., vol. 69 (1968) p. 76074X.|
|3||Lange, Chem. Abst., vol. 69 (1968) p. 99303K.|
|4||*||Lange, Chem. Abst., vol. 69 (1968) p. 99303K.|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US6248767||Sep 26, 1997||Jun 19, 2001||Texas Biotechnology Corp.||Formulation of sulfonamides for treatment of endothelin-mediated disorders|
|US6342610||Apr 4, 1996||Jan 29, 2002||Texas Biotechnology Corp.||N-aryl thienyl-, furyl-, and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin|
|US6362009||Nov 21, 1997||Mar 26, 2002||Merck & Co., Inc.||Solid phase synthesis of heterocycles|
|US6420567||Sep 26, 1997||Jul 16, 2002||Texas Biotechnology Corporation||N-heteroaryl aryl-substituted thienyl-furyl-and pyrrolyl-sulfonamides and derviatives thereof that modulate the activity of endothelin|
|US6432994||Apr 2, 1998||Aug 13, 2002||Texas Biotechnology Corporation||Sulfonamides for treatment of endothelin-mediated disorders|
|US6458805||Feb 23, 2001||Oct 1, 2002||Texas Biotechnology Corporation||Formulation of sulfonamides for treatment of endothelin-mediated disorders|
|US6638977||Nov 19, 1999||Oct 28, 2003||Corvas International, Inc.||Plasminogen activator inhibitor antagonists|
|US6677473||Nov 17, 2000||Jan 13, 2004||Corvas International Inc||Plasminogen activator inhibitor antagonists|
|US6683103||Dec 20, 2001||Jan 27, 2004||Texas Biotechnology Corporation||Sulfonamides for treatment of endothelin-mediated disorders|
|US7053210||Jul 2, 2003||May 30, 2006||Health Research, Inc.||Efficient synthesis of pyropheophorbide a and its derivatives|
|US7115640||Nov 18, 2003||Oct 3, 2006||X-Ceptor Therapeutics, Inc.||Heterocyclic modulators of nuclear receptors|
|US7166719||Jun 27, 2003||Jan 23, 2007||Health Research, Inc.||Fluorinated photosensitizers related to chlorins and bacteriochlorins for photodynamic therapy|
|US7244739||May 14, 2004||Jul 17, 2007||Torreypines Therapeutics, Inc.||Compounds and uses thereof in modulating amyloid beta|
|US7381736||Sep 2, 2005||Jun 3, 2008||Metabasis Therapeutics, Inc.||Thiazole and thiadiazole inhibitors of tyrosine phosphatases|
|US7420000||Sep 10, 2004||Sep 2, 2008||University Of Southern California||Amino phosphonate and amino bis-phosphonate derivatives|
|US7501509||Jun 14, 2006||Mar 10, 2009||Health Research, Inc.||Water soluble tetrapyrollic photosensitizers for photodynamic therapy|
|US7652001||Feb 7, 2005||Jan 26, 2010||The Regents Of The University Of California||Pharmacologically active agents containing esterified phosphonates and methods for use thereof|
|US7652044||Jun 2, 2004||Jan 26, 2010||Novartis A.G.||P-38 inhibitors|
|US7683193||Apr 4, 2006||Mar 23, 2010||University Of Southern California||Benzo lipoxin analogues|
|US7767429||Mar 5, 2004||Aug 3, 2010||Halozyme, Inc.||Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof|
|US7781442||Jul 17, 2007||Aug 24, 2010||Neurogenetic Pharmaceuticals, Inc.||Compounds and uses thereof in modulating amyloid beta|
|US7799808||Jun 19, 2007||Sep 21, 2010||Neurogenetic Pharmaceuticals, Inc.||α-Haloketone derivatives of imidazolyl-substituted aromatic compounds and compounds prepared therefrom|
|US7820143||Feb 19, 2009||Oct 26, 2010||Health Research, Inc.||Water soluble tetrapyrollic photosensitizers for photodynamic therapy|
|US7829081||Mar 4, 2010||Nov 9, 2010||Halozyme, Inc.||Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases|
|US7846431||Mar 4, 2010||Dec 7, 2010||Halozyme, Inc.||Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases|
|US7871607||Feb 23, 2005||Jan 18, 2011||Halozyme, Inc.||Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases|
|US7897140||Jun 30, 2006||Mar 1, 2011||Health Research, Inc.||Multi DTPA conjugated tetrapyrollic compounds for phototherapeutic contrast agents|
|US7998986||Dec 20, 2002||Aug 16, 2011||Exelixis Patent Company Llc||Modulators of LXR|
|US8013001||Dec 17, 2008||Sep 6, 2011||Exelixis, Inc.||Modulators of LXR|
|US8017629||Aug 23, 2010||Sep 13, 2011||Neurogenetic Pharmaceuticals, Inc.||Compounds and uses thereof in modulating amyloid β|
|US8105586||Jun 15, 2010||Jan 31, 2012||Halozyme, Inc.||Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases|
|US8115023||Feb 23, 2010||Feb 14, 2012||University Of Southern California||Benzo lipoxin analogues|
|US8119680||Sep 3, 2010||Feb 21, 2012||Neurogenetic Pharmaceuticals, Inc.||α-Haloketone derivatives of imidazolyl-substituted aromatic compounds and compounds prepared therefrom|
|US8138361||Dec 27, 2006||Mar 20, 2012||The Trustees Of The University Of Pennsylvania||C-10 carbamates of taxanes|
|US8193167||Dec 10, 2009||Jun 5, 2012||The Regents Of The University Of California||Pharmacologically active agents containing esterified phosphonates and methods for use thereof|
|US8193357||Jun 12, 2006||Jun 5, 2012||Ligand Pharmaceuticals Incorporated||Androgen receptor modulator compounds|
|US8202517||Feb 20, 2009||Jun 19, 2012||Halozyme, Inc.||Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof|
|US8222257||Mar 30, 2006||Jul 17, 2012||The Regents Of The University Of California||Phosphono-pent-2-en-1-yl nucleosides and analogs|
|US8242117||Nov 19, 2010||Aug 14, 2012||Novartis Ag||5-membered heterocycle-based p38 kinase inhibitors|
|US8257699||Dec 15, 2011||Sep 4, 2012||Halozyme, Inc.||Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases|
|US8303983||Jan 14, 2010||Nov 6, 2012||Sdg, Inc.||Targeted liposomal drug delivery system|
|US8354446||Dec 12, 2008||Jan 15, 2013||Ligand Pharmaceuticals Incorporated||Selective androgen receptor modulators (SARMs) and uses thereof|
|US8404728||Jul 29, 2010||Mar 26, 2013||Mayo Foundation For Medical Education And Research||Small-molecule botulinum toxin inhibitors|
|US8410160||Jun 22, 2012||Apr 2, 2013||Novartis Ag||5-membered heterocycle-based P38 kinase inhibitors|
|US8426587||Nov 19, 2008||Apr 23, 2013||Pharmaxis Ltd.||Haloallylamine inhibitors of SSAO/VAP-1 and uses therefor|
|US8431124||Apr 16, 2009||Apr 30, 2013||Halozyme, Inc.||Methods for treating a disease characterized by an excess of hyaluronan by administering a soluble hyaluronidase glycoprotein (sHASEGP)|
|US8431380||Feb 20, 2009||Apr 30, 2013||Halozyme, Inc.||Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof|
|US8440705||Sep 16, 2005||May 14, 2013||Whitehead Institute For Biomedical Research||Compounds, compositions and methods of inhibiting alpha-synuclein toxicity|
|US8450470||Jun 3, 2009||May 28, 2013||Halozyme, Inc.|
|US8492428||Sep 20, 2006||Jul 23, 2013||Mayo Foundation For Medical Education And Research||Small-molecule botulinum toxin inhibitors|
|US8519158||Mar 11, 2005||Aug 27, 2013||Ligand Pharmaceuticals Incorporated||Androgen receptor modulator compounds and methods|
|US8580252||Jul 6, 2012||Nov 12, 2013||Halozyme, Inc.||Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases|
|US8580811||Mar 6, 2012||Nov 12, 2013||Ligand Pharmaceuticals Incorporated||Androgen receptor modulator methods|
|US8580838||Feb 25, 2013||Nov 12, 2013||Novartis Ag||5-membered heterocycle-based p38 kinase inhibitors|
|US8592445||Jun 22, 2012||Nov 26, 2013||Map Pharmaceuticals, Inc.||Iso-ergoline derivatives|
|US8604035||Jun 22, 2012||Dec 10, 2013||Map Pharmaceuticals, Inc.||Fluoroergoline analogs|
|US8710092||Dec 23, 2010||Apr 29, 2014||Map Pharmaceuticals, Inc.||Substituted indolo 4,3 FG quinolines useful for treating migraine|
|US8722699||Oct 3, 2013||May 13, 2014||Map Pharmaceuticals, Inc.||Iso-ergoline derivatives|
|US8748633||Oct 23, 2012||Jun 10, 2014||Ligand Pharmaceuticals Incorporated||Selective androgen receptor modulators (SARMs) and uses thereof|
|US8765685||May 16, 2012||Jul 1, 2014||Halozyme, Inc.||Methods for treating edema by administering a Soluble Hyaluronidase Glycoprotein (sHASEGP)|
|US8772246||Oct 18, 2012||Jul 8, 2014||Halozyme, Inc.|
|US8791155||Sep 26, 2011||Jul 29, 2014||Edison Pharmaceuticals, Inc.||Chroman derivatives|
|US8802881||Feb 13, 2012||Aug 12, 2014||University Of Southern California||Benzo lipoxin analogues|
|US8841448||Oct 7, 2013||Sep 23, 2014||Map Pharmaceuticals, Inc.||Fluoroergoline analogs|
|US8865918||Aug 23, 2013||Oct 21, 2014||Ligand Pharmaceuticals Incorporated||Androgen receptor modulator compounds and methods|
|US8871460||Nov 8, 2010||Oct 28, 2014||Neurogenetic Pharmaceuticals, Inc.||Gamma-secretase modulatory compounds, methods for identifying same, and uses therefor|
|US8895743||Dec 19, 2013||Nov 25, 2014||Map Pharmaceuticals, Inc.||Methysergide derivatives|
|US8927249||Dec 9, 2009||Jan 6, 2015||Halozyme, Inc.||Extended soluble PH20 polypeptides and uses thereof|
|US8927567||Oct 7, 2013||Jan 6, 2015||Map Pharceuticals, Inc.||Fluoroergoline analogs|
|US8933093||Oct 7, 2013||Jan 13, 2015||Map Pharmaceuticals, Inc.||Fluoroergoline analogs|
|US8946420||Jun 22, 2012||Feb 3, 2015||Map Pharmaceuticals, Inc.||Neuromodulatory compounds|
|US8969374||Oct 3, 2013||Mar 3, 2015||Map Pharmaceuticals, Inc.||Iso-ergoline derivatives|
|US9012640||Jun 22, 2012||Apr 21, 2015||Map Pharmaceuticals, Inc.||Cabergoline derivatives|
|US9139520||Apr 28, 2014||Sep 22, 2015||Ligand Pharmaceuticals Incorporated||Selective androgen receptor modulators (SARMs) and uses thereof|
|US9150593||Dec 12, 2014||Oct 6, 2015||Map Pharmaceuticals, Inc.||Fluoroergoline analogs|
|US9169214||Mar 14, 2013||Oct 27, 2015||The Board Of Trustees Of The Leland Stanford Junior University||Compounds and compositions that bind and stabilize transthyretin and their use for inhibiting transthyretin amyloidosis and protein-protein interactions|
|US9211315||May 7, 2014||Dec 15, 2015||Halozyme, Inc.||Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases|
|US9359285||Oct 20, 2014||Jun 7, 2016||Ligand Pharmaceuticals Incorporated||Androgen receptor modulator compounds and methods|
|US9365591||Aug 28, 2015||Jun 14, 2016||Map Pharmaceuticals, Inc.||Fluoroergoline analogs|
|US9403815||Jun 24, 2011||Aug 2, 2016||The Regents Of The University Of California||Compounds and uses thereof in modulating levels of various amyloid beta peptide alloforms|
|US9562223||Feb 26, 2014||Feb 7, 2017||Halozyme, Inc.||Methods for reducing intraocular pressure by administering a soluble hyaluronidase glycoprotein (sHASEGP)|
|US9573880||Aug 1, 2014||Feb 21, 2017||University Of Southern California||Benzo lipoxin analogues|
|US9642838||Oct 6, 2015||May 9, 2017||The Board Of Trustees Of The Leland Standford Junior University||Compounds and compositions that bind and stabilize transthyretin and their use for inhibiting transthyretin amyloidosis and protein-protein interactions|
|US9657020||Jan 20, 2016||May 23, 2017||Xoc Pharmaceuticals, Inc.||Ergoline compounds and uses thereof|
|US9675583||Aug 14, 2015||Jun 13, 2017||Ligand Pharmaceuticals Incorporated||Selective androgen receptor modulators (SARMS) and uses thereof|
|US9676776||Jan 20, 2016||Jun 13, 2017||Xoc Pharmaceuticals, Inc.||Isoergoline compounds and uses thereof|
|US9677061||Dec 21, 2010||Jun 13, 2017||Halozyme, Inc.|
|US9677062||Dec 28, 2011||Jun 13, 2017||Halozyme, Inc.||Hyaluronidase and factor VIII compositions|
|US9732038||Mar 14, 2013||Aug 15, 2017||Mayo Foundation For Medical Education And Research||Pyrazole derivatives as inhibitors of STAT3|
|US20040044198 *||Jul 2, 2003||Mar 4, 2004||Pandey Ravindra K.||Efficient synthesis of pyropheophorbide a and its derivatives|
|US20040180942 *||Nov 18, 2003||Sep 16, 2004||X-Ceptor Therapeutics, Inc.||Heterocyclic modulators of nuclear receptors|
|US20040268425 *||Mar 5, 2004||Dec 30, 2004||Deliatroph Pharmaceuticals, Inc.|
|US20050065118 *||Oct 16, 2002||Mar 24, 2005||Jing Wang||Organosulfur inhibitors of tyrosine phosphatases|
|US20050070538 *||May 14, 2004||Mar 31, 2005||Soan Cheng||Compounds and uses thereof in modulating amyloid beta|
|US20050148534 *||Sep 22, 2004||Jul 7, 2005||Castellino Angelo J.||Small molecule compositions and methods for increasing drug efficiency using compositions thereof|
|US20050192246 *||Feb 7, 2005||Sep 1, 2005||Hostetler Karl Y.||Pharmacologically active agents containing esterified phosphonates and methods for use thereof|
|US20050260186 *||Feb 23, 2005||Nov 24, 2005||Halozyme, Inc.||Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases|
|US20060104968 *||Sep 27, 2005||May 18, 2006||Halozyme, Inc.||Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases|
|US20060135483 *||Jul 8, 2005||Jun 22, 2006||Cheruvallath Zacharia S||Oxygen/nitrogen heterocycle inhibitors of tyrosine phosphatases|
|US20060135773 *||Jun 17, 2005||Jun 22, 2006||Semple Joseph E||Trisubstituted nitrogen modulators of tyrosine phosphatases|
|US20060270734 *||Apr 4, 2006||Nov 30, 2006||Petasis Nicos A||Benzo lipoxin analogues|
|US20070053840 *||Jun 30, 2006||Mar 8, 2007||Health Research, Inc.||Multi DTPA conjugated tetrapyrollic compounds for phototherapeutic contrast agents|
|US20070249833 *||Jun 19, 2007||Oct 25, 2007||Torreypines Therapeutics Inc.||Compounds and uses thereof in modulating amyloid beta|
|US20070260058 *||Jul 17, 2007||Nov 8, 2007||Torreypines Therapeutics Inc.||Compounds and Uses Thereof in Modulating Amyloid Beta|
|US20080200371 *||Mar 28, 2008||Aug 21, 2008||Cheruvallath Zacharia S||Thiazole and thiadiazole inhibitors of tyrosine phosphatases|
|US20090030027 *||Jun 12, 2006||Jan 29, 2009||Ligand Pharmaceuticals Incorporated||Androgen Receptor Modulator Compounds and Methods|
|US20090123367 *||Feb 23, 2006||May 14, 2009||Delfmems||Soluble Glycosaminoglycanases and Methods of Preparing and Using Soluble Glycosaminoglycanases|
|US20090156545 *||Mar 30, 2006||Jun 18, 2009||Hostetler Karl Y||Substituted Phosphate Esters of Nucleoside Phosphonates|
|US20090181013 *||Feb 20, 2009||Jul 16, 2009||Bookbinder Louis H|
|US20090181032 *||Feb 20, 2009||Jul 16, 2009||Bookbinder Louis H|
|US20090214505 *||Apr 16, 2009||Aug 27, 2009||Bookbinder Louis H|
|US20090253175 *||Jun 3, 2009||Oct 8, 2009||Bookbinder Louis H|
|US20090264421 *||Mar 18, 2009||Oct 22, 2009||Bible Keith C||Methods and Compositions for Treating Cancer|
|US20090264455 *||Jun 12, 2006||Oct 22, 2009||Ligand Pharmaceuticals Incorporated||Androgen Receptor Modulator Compounds and Methods|
|US20090306014 *||Dec 27, 2006||Dec 10, 2009||Acidophil Llc||C-10 carbamates of taxanes|
|US20100004298 *||Sep 11, 2009||Jan 7, 2010||Qing Dong||P-38 inhibitors|
|US20100098640 *||Jun 20, 2006||Apr 22, 2010||Cohen Seth M||Multidentate Pyrone-Derived Chelators for Medicinal Imaging and Chelation|
|US20100152290 *||Feb 23, 2010||Jun 17, 2010||Petasis Nicos A||Benzo Lipoxin Analogues|
|US20100196423 *||Mar 4, 2010||Aug 5, 2010||Bookbinder Louis H||Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases|
|US20100209492 *||Jan 14, 2010||Aug 19, 2010||Sdg, Inc. (An Ohio Corporation)||Targeted Liposomal Drug Delivery System|
|US20100256129 *||Dec 12, 2008||Oct 7, 2010||Lin Zhi||Selective androgen receptor modulators (sarms) and uses thereof|
|US20100260778 *||Sep 20, 2006||Oct 14, 2010||Yuan-Ping Pang||Small-molecule botulinum toxin inhibitors|
|US20100273776 *||Mar 29, 2007||Oct 28, 2010||FOLDRx PHARMACEUTICALS, INC||Inhibition of alpha-synuclein toxicity|
|US20100298330 *||Nov 19, 2008||Nov 25, 2010||Pharmaxis Ltd.||Haloallylamine inhibitors of ssao/vap-1 and uses therefor|
|US20100324032 *||Aug 23, 2010||Dec 23, 2010||Neurogenetic Pharmaceuticals, Inc.||Compounds and uses thereof in modulating amyloid beta|
|US20100331551 *||Sep 3, 2010||Dec 30, 2010||Neurogenetic Pharmaceuticals, Inc||Alpha-haloketone derivatives of imidazolyl-substituted aromatic compounds and compounds prepared therefrom|
|US20110008309 *||Jun 15, 2010||Jan 13, 2011||Halozyme, Inc.||Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases|
|US20110071152 *||Nov 19, 2010||Mar 24, 2011||Fryszman Olga M||5-membered heterocycle-based p38 kinase inhibitors|
|US20110152280 *||Dec 23, 2010||Jun 23, 2011||Map Pharmaceuticals, Inc.||Novel ergoline analogs|
|US20110152359 *||Dec 21, 2010||Jun 23, 2011||Bookbinder Louis H||Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising threreof|
|USRE43274||Jan 23, 2009||Mar 27, 2012||Health Research, Inc.||Fluorinated photosensitizers related to chlorins and bacteriochlorins for photodynamic therapy|
|EP1911754A1||Aug 12, 2004||Apr 16, 2008||Takeda Pharmaceutical Company Limited||Dipeptidyl peptidase inhibitors|
|EP2113500A1||Oct 31, 2007||Nov 4, 2009||Takeda Pharmaceutical Company Limited||MAPK/ERK kinase inhibitors|
|EP2133349A1||Oct 10, 2006||Dec 16, 2009||Takeda San Diego, Inc.||Kinase inhibitors|
|EP2145877A2||Oct 8, 2007||Jan 20, 2010||Takeda Pharmaceutical Company Limited||Aurora Kinase inhibitors|
|EP2145878A2||Oct 8, 2007||Jan 20, 2010||Takeda Pharmaceutical Company Limited||Aurora Kinase inhibitors|
|EP2163643A1||Mar 5, 2004||Mar 17, 2010||Halozyme, Inc.|
|EP2177620A1||Mar 5, 2004||Apr 21, 2010||Halozyme, Inc.|
|EP2223925A1||Oct 8, 2007||Sep 1, 2010||Takeda Pharmaceutical Company Limited||Kinase inhibitors|
|EP2292663A2||Aug 24, 2007||Mar 9, 2011||Kyowa Hakko Kirin Co., Ltd.||Antagonistic human light-specific human monoclonal antibodies|
|EP2311842A2||Jun 23, 2009||Apr 20, 2011||Takeda Pharmaceutical Company Limited||PI3K/M TOR inhibitors|
|EP2311973A1||Mar 5, 2004||Apr 20, 2011||Halozyme, Inc.|
|EP2314584A1||May 20, 2005||Apr 27, 2011||Foldrx Pharmaceuticals, Inc.||2-(heteroaryl)-benzoxazole compounds and derivatives, compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding|
|EP2330213A1||Mar 5, 2004||Jun 8, 2011||Halozyme, Inc.|
|EP2405015A2||Mar 5, 2004||Jan 11, 2012||Halozyme, Inc.|
|EP2415767A1||Mar 26, 2010||Feb 8, 2012||Takeda Pharmaceutical Company Limited||Poly (ADP-ribose) Polymerase (PARP) Inhibitors|
|EP2433634A2||Sep 16, 2005||Mar 28, 2012||The Whitehead Institute for Biomedical Research||Compounds, compositions and methods of inhibiting a-synuclein toxicity|
|EP2457895A1||Jul 12, 2005||May 30, 2012||Idun Pharmaceuticals, Inc.||Tetrapeptide analogs|
|EP2457896A1||Jul 12, 2005||May 30, 2012||Idun Pharmaceuticals, Inc.||Tripeptides as caspase modulators|
|EP2484696A1||Aug 24, 2007||Aug 8, 2012||Kyowa Hakko Kirin Co., Ltd.||Antagonistic human light-specific human monoclonal antibodies|
|EP2489656A1||Dec 12, 2008||Aug 22, 2012||Ligand Pharmaceuticals Inc.||Selective androgen receptor modulators (sarms) and uses thereof|
|EP2564850A1||Sep 24, 2008||Mar 6, 2013||Takeda Pharmaceutical Company Limited||Polo-like kinase inhibitors|
|EP2805953A1||Dec 16, 2005||Nov 26, 2014||Takeda Pharmaceutical Company Limited||Dipeptidyl peptidase inhibitors|
|EP2947100A1||Jan 6, 2010||Nov 25, 2015||Curelon LLC||Oral compositions for the treatment or the prevention of infections by E. Coli|
|EP3009517A1||Mar 5, 2004||Apr 20, 2016||Halozyme, Inc.||Soluble hyaluronidase glycoprotein (shasegp), process for preparing the same, uses and pharmaceutical compositions comprising thereof|
|EP3045472A1||Feb 23, 2006||Jul 20, 2016||Halozyme, Inc.||Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases|
|EP3064217A1||Jan 6, 2010||Sep 7, 2016||Curelon LLC||Compositions comprising protease, amylase and lipase for use in the treatment of staphylococcus aureus infections|
|WO2003076418A1||Mar 4, 2003||Sep 18, 2003||X-Ceptor Therapeutics, Inc.||Quinazolinone modulators of nuclear receptors|
|WO2009066152A2||Nov 19, 2008||May 28, 2009||Pharmaxis Ltd.||Haloallylamine inhibitors of ssao/vap-1 and uses therefor|
|WO2011014681A1||Jul 29, 2010||Feb 3, 2011||Takeda Pharmaceutical Company Limited||Poly (ADP-Ribose) Polymerase (PARP) INHIBITORS|
|WO2011041293A1||Sep 28, 2010||Apr 7, 2011||Takeda Pharmaceutical Company Limited||Pyrazolo [1, 5-a] pyrimidine derivatives as apoptosis signal-regulating kinase 1 inhibitors|
|WO2011057214A2||Nov 8, 2010||May 12, 2011||Neurogenetic Pharmaceuticals, Inc.||Gamma-secretase modulatory compounds, methods for identifying same, and uses therefor|
|WO2011069002A1||Dec 2, 2010||Jun 9, 2011||Alquest Therapeutics, Inc.||Organoselenium compounds and uses thereof|
|WO2011097079A1||Jan 21, 2011||Aug 11, 2011||Takeda Pharmaceutical Company Limited||Apoptosis signal-regulating kinase 1 inhibitors|
|WO2013037482A1||Sep 11, 2012||Mar 21, 2013||Phenex Pharmaceuticals Ag||Farnesoid x receptor agonists for cancer treatment and prevention|
|WO2013163675A1||Apr 5, 2013||Nov 7, 2013||Pharmaxis Ltd.||Substituted 3-haloallylamine inhibitors of ssao and uses thereof|
|WO2016139482A1||Mar 3, 2016||Sep 9, 2016||Kymab Limited||Antibodies, uses & methods|
|U.S. Classification||514/174, 514/573, 514/772, 514/613|
|International Classification||A61K31/557, A61K47/08|
|Cooperative Classification||A61K31/557, A61K47/08|
|European Classification||A61K47/08, A61K31/557|