|Publication number||US3087860 A|
|Publication date||Apr 30, 1963|
|Filing date||Dec 19, 1958|
|Priority date||Dec 19, 1958|
|Publication number||US 3087860 A, US 3087860A, US-A-3087860, US3087860 A, US3087860A|
|Inventors||Endicott Clarence J|
|Original Assignee||Abbott Lab|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (16), Referenced by (84), Classifications (11)|
|External Links: USPTO, USPTO Assignment, Espacenet|
United States Patent 07'' 3,087,860 METHOD OF PROLONGING RELEASE OF DRUG FROM A PRECOMPRESSED SOLID CARRIER Clarence J. Endicott, Winthrop Harbor, Ill., assignor to Abbott Laboratories, North Chicago, 111., a corporation of Illinois No Drawing. Filed Dec. 19, 1958, Ser. No. 781,433 11 Claims. (Cl. 167-82) This invention relates to a novel method of prolonging the release of a drug from a solid carrier. More particularly, the invention relates to the vapor treatment of a drug composition dispersed in a plastic carrier. This treatment fuses the individual particles of plastic into a continuous network of plastic which impedes the release of the drug from the carrier when such a composition is administered orally.
It has always been recognized in the medical art that the administration of drugs by the oral route is to be preferred and in recent years more and more emphasis has been placed on the oral administration of drugs. There are reasons why many drugs cannot be administered satisfactorily in their simplest form. For example, the drug may be too readily absorbed with the consequent danger from toxic dosage. Secondly, it may be too readily excreted and pass out of the body before the therapeutic effect can be realized or the drug may be effective but prolongation of its effect is desired to avoid multiple dosages.
Numerous attempts have been made to provide a dosage form which will solve the foregoing problems but up to the present time none of these has proven entirely satisfactory. For example, enteric coatings have been applied for many years to a wide variety of drugs in an attempt to protect the drug from gastric secretions, or to protect the stomach from the harsh effect of the drug. Enteric coatings have employed many kinds of materials and all are designed to be resistant to gastric secretions, but must be readily disintegrated in the intestinal tract in order for the drug to become effective. In every instance the enteric coating is designed to prevent release of drug in the stomach and to be destroyed or broken up in the intestinal tract. Enteric cOatings as a class depend upon some type of chemical action or reaction for their disintegration.
Another class of protective coating for medieaments is the type known as time-disintegration coatings. In these coatings a class of materials is used which is dissolved or distinguished slowly as the tablet passes through the stomach and intestine, and an amount of coating is used which is designed to allow release of the drug after a certain period of time in the body. Due to the tremendous differences in the operation of the gastrointestinal mechanism in different persons the time-disintegration coating does not work the same way in every person but rather is designed to give results based on averages.
A variation of the time-disintegration dosage form just described is one in which particles of a medicament are coated with a varying number of layers of a material which will be slowly washed away or destroyed by the gastro-intestinal fluids. In such a dosage form a portion of the drug has little or no coating for initial response, thin coatings are used for a quick follow-up response and thicker coatings are used for a delayed response.
Time-disintegration coatings as a class depend for their disintegration upon the effects of agents found in the gastro-intest-inal fluids. The enzymes, fat-solubilizers and emulsifiersin these fluids hasten the breaking-up or wearing-away of the coatings.
It is a principal object of the present invention to pro- 3,087,860 Patented Apr. 30, 1963 vide a method for the preparation of an orally effective dosage form in which the drug will be slowly released in the body.
Another object of the invention is to provide a method for the vapor treatment of a drug composition dispersed in a plastic carrier which will coalesce the individual particles of plastic to impede the release of the drug when such a composition is orally administered.
A further object of the invention is to provide a method for the preparation of an oral dosage form from which the drug will be slowly released by a substantially physical process of dissolving drug out of a solid, inert body independently of the digestive process.
Other objects and many of the inherent advantages of the present invention will become more apparent throughout the following specification and appended claims.
In the accomplishment of the foregoing objects and in accordance with the practice of this invention there is now provided a method for the vapor treatment of a combination of a drug and, if desired, a water-soluble excipient dispersed uniformly in a body of a non-toxic synthetic plastic material. Such treatment produces a continuous network within the carrier and makes it less susceptible to disintegration when such a drug combination is orally ingested. In general, the method consists of exposing a compressed mixture (conveniently in table form) of drug and plastic to the vapors of a volatile organic solvent for the plastic in a confined space for a period of time suflicient to result in softening of the surface of said plastic.
Suitable solvents include methylene chloride, ethyl acetate, ethylene dichloride and toluene. In a preferred method of operation, acetone is employed as the solvent. The compressed mixture of drug and plastic is exposed in a confined space at room temperature and atmospheric pressure for a period of from 3 to 24 hours. Alternatively, the vapor treatment may be carried out at temperatures of about 100 F. at atmospheric pressure or at considerably higher temperatures and under vacuum.
Upon drying the treated tablet, the plastic particles adhere to one another more firmly forming a porous body having a network of continuous interstices throughout the tablet. The plastic body resists disintegration during exposure to water. Before solvent vapor treatment, the
, plastic particles are so loosely held together that the tablets disintegrate within a very short time. Thus, it is believed that the treatment results in a partial solubilization of the individual particles of plastic by the solvent vapor and a fusion of one particle of plastic to another. When such a composition comes into contact with an aqueous liquid the drug is leached or diffused out of the plastic body. The amount of drug released in the early stages of the leaching process is sufficient to provide the desired initial pharmacologic response and the amount of drug released thereafter will sustain the pharmacologic response over an extended period of time. Because the releasing action is entirely physical, rather than chemical, the results are readily predictable.
The term drug is used herein in its broadest sense as indicating any substance or composition which will give a pharmacologic response. When it is said that the drug is water soluble it is meant to indicate that the drug must be soluble in aqueous liquids to at least a certain small extent but drugs which are readily soluble in water will, of course, make up the preferred group. Methamphetamine salts, hexocyclium methylsulfate, paraamino benzoic acid, ephedrine, mannitol hexanitrate, amphetamine, erythromycin salts, penicillin salts, pentobarbital, phenobarbital, atropine, belladonna, theophylline, sex hormones, hydantoins, trimethadione, watersoluble vitamins such as B and C, benzazoline, toluidine blue and related drugs are representative of the broad class of drugs which may be incorporated in compositions suitable for treatment by this new method.
The plastics to which this invention pertains may be any synthetic resinous of polymeric material which is substantially inert to gastro-intestinal liquids and which, of course, is essentially non-toxic and can be ingested without danger. The plastic mass or body may be referred to as an orally ingestible plastic carrier, in which the drug is dispersed. It is desirable that the drug be uniformly dispersed throughout the body or mass of the carrier in order that uniformity of results may be obtained. In a preferred form of the invention, it is desirable to use a plastic carrier which is not only substantially water insoluble but which will be excreted substantially unchanged except for the loss of the drug therefrom.
The polymers suitable for use in this invention must be resistant to flow, sintering or blocking at temperatures likely to be encountered in storage. While rubbery materials can be used, the manufacture of the finished product is easier if the polymer is hard, i.e., in a glassy or crystalline state at ambient temperature. Since the temperature at Which pharmaceutical products may be stored may rise as high as 105 F., the glass point of a suitable polymer should preferably be not much lower than 105 F. The glass point is defined in Flory, Principles of Polymer Chemistry, p. 56, Cornell University Press, 1953. Briefly, it is the midpoint of the narrow temperature region above which an amorphous polymer exists in a viscous or rubbery condition and below which it is hard and relatively brittle.
There are numerous polymers and copolymers which can be used successfully in this invention as will be evident to those skilled in the art. A few examples are polyethylene, polymethylmethacrylate, copolymers of methylmethacrylate and alkyl acrylates, polyvinylacetate, polyhexamethylene adipamide and the like.
The polymers can be prepared by bulk, solution, suspension, or emulsion polymerization. If the last method is used, the polymer may be coagulated into solid particles which can be readily mixed with a drug or a drug may be admixed before coagulation as will be more fully discussed hereinafter.
In the polymerization procedure, it is desirable in some cases to use a step or steps in which impurities, if present, are removed. There should be removed inhibitor, if used, residual monomer or monomers, and any remaining polymerization initiator. Methods for accomplishing these ends are known in the art. They include distillation in its various aspects such as distillation with steam or under low pressure, washing and extraction.
The composition employed in the method of this invention may be described as having discrete particles of a drug dispersed in a matrix of a plastic carrier. This composition is to be distinguished from a plastic tablet coating in which the coating completely surrounds the drug and prevents access of liquids to the drug until the coating is disrupted or destroyed. In the present instance, the plastic takes the form of a foraminous body with drug contained in the pockets or voids, but the drug is accessible to liquids and may be removed from the plastic body by a leaching or washing action without materially affecting the phyiscal condition of the plastic body.
One may add sodium chloride or other water-soluble, component or ingredient to increase the water permeability of the composition. Other water-soluble excipients or adjuvants which may be employed include dextrose, acacia, sucrose, polyethylene glycols, sorbitol, urea, polyvinylpyrrolidone, inositol, lactose, mannitol, methocel, calcium chloride, pectin and the like.
The composition employed in the method of this invention can be made in a number of ways which will be apparent to one skilled in the plastics art. One suitable way of making the composition is to thoroughly blend a plastic in powder or granular form with the drug in crystalline or granular form and then subject the mixture to heat and pressure so that the composition is converted into a solid body or mass having the drug dispersed therein. It is possible by the use of selected proportions of particles having different sizes to arrive at any desired rate of diffusion or leaching. This is an important and highly desirable feature since it enables the compounder to adjust the rate of release of the drug to a given set of conditions.
Another method is to disperse the drug in a liquid monomer, and polymerize the mass, thereby achieving an excellent dispersion of the drug in the plastic, which may then be comminuted to desired size. This method may be varied by using mixtures of monomers, and by adding polyfunctional monomers, which result in a cross-linked plastic, insolu-be in most solvents. By means of this latter technique, normally water-soluble polymers and very hydrophilic polymers, such as polyacrylic acid, may be employed in the invention.
Still other methods are contemplated. In addition to incorporation of the drug by milling or by mixing and extruding the drug-plastic combination, a drug of limited water solubility may be finely ground and suspended in a latex or aqueous dispersion of an appropriate plastic. The latex may then be coagulated by known procedures to give a finely divided crumb in which the plastic and drug are intimately associated. Alternatively, a dispersion or solution of a drug in such a latex may be spray dried or drum dried and the solid product ground and screened to give a suitable product. In another method the plastic is dissolved in a solvent solution, the drug is dispersed or dissolved therein and the suspension or solution cast as a film by known techniques. The film can be ground and screened to proper size.
The amount of drug which is suspended or dispersed in the plastic mass may be varied at will from a small but significant amount capable of giving a pharmacologic response up to the saturation point beyond which the composition will no longer have its characteristic properties as a plastic mass. In one instance it was found that up to by weight of drug based on the total weight of the composition can be employed. It will be apparent that the concentration of the drug, the particle size of the composition and the water permeability of the plastic mass provide a great deal of control over the response of the drug and may be interrelated in such a way as to give the compounder great leeway in the preparation of tailored compositions.
The composition employed in the vapor treatment method of this invention may be prepared by grinding or otherwise comminuting the plastic mass having the drug embedded therein to a desired particle size or range of particle sizes and mixing, combining or incorporating in a pharmaceutical carrier. Particle size in an important aspect of the invention since the rate of diffusion or leaching out of the drug from a given plastic after vapor treatment will be slower from a small particle than from a large particle. The particles may be recombined with tableting adjuvants in the form of conventional pharmaceutical tablets.
The following examples illustrate the invention but are not to be construed as a limitation thereof.
Example I Mg. Sodium p-aminobenzoate 8.26 Sodium chloride 24.80
Methylacrylate-methylmethacrylate copolymer 48.6
These tablets were exposed to acetone vapor in a closed container for 24 hours at room temperature and after drying were tested for release of the drug by exposure to water with the following results:
6 v r ing the tablets with water. The results are tabulated below.
P t 1 Percent Percent 5 Time of exposure in minutes f fi hg ti s true of exposure in minutes release of release of tr atment;
dtrngtbeforte grug after; 1'82, D1611 rea men a 15 29 12 22 ii 56 23 120 47 73 36 240 69 2% 480 82 90 81 Before the acetone vapor treatment, these tablets release as much as 80% of the drug in one hour or less 1S dapparent from i abgve l zl thefidmg Is 15 when exposed to water. In addition, the tablets disintei fi if g i 2 o g i er Z grate rapidly before treatment but remain intact after one t e P as w par 16 m w 6 treatment even when all the drug is leached from the the drug 1s uniformly dispersed form a continuous net- 1 p astic carrier. work of VOld spaces throughout the tablets wh1ch resist Example 1V dismtegration and permit the drug to be leached gradu- 20 ally from the plastic body. The plastic body is com- In another p r compressed tablets were p pletely intact as a single entity at the end of the leaching pared 111 a manner Wherem the amouhls of process each component are given below on a per tablet basis:
Example II Compressed tablets wherein all ingredients and amounts Methamphetamine hydrochloride 5 are on a per tablet basis were prepared in the normal Polyvmylpyrrohdone 26-41 manner; Methylacrylate-methylmethacrylate copolymer 77.37 M Talc t 5.36 Hexocyclium methylsulfate 7 5 Magnesium stearate Mithylaerylale'methylmethael'ylale P Y 30 These tablets were treated with acetone vapors in a vace uum chamber for 5 hours at a temperature of 30 C. Magnesium stearate 3-3 and a pressure of 240 mm. of mercury. The tablets were The tablets were exposed to acetone vapor in a closed then alr-dried overnight and finally oven-dried at 140 F. container for 24 hours at room tempera/[ma The dried for 48 hours to remove all traces of acetone. The treated tablets were then tested for the release of the drug by exggg g ggig gggg g; g: lg f ig 2$ 2g:
osure to water th h f ll sults: P W t e o owmg re plastic carrier remained mtact after all the drug had been removed. Before the vapor treatment, the compressed I Percent Percent tablets disintegrated rapidly in water and released the drug Tune of exposure in minutes dgellgatsgfgie toef 40 within 30 to 60 minutes treatment treatment In still other experiments, it was found that satisfactory results could be obtained so far as the gradual release of 23 i the drug and resistance to disintegration of the plastic 32 carrier were concerned when the vapor treatment of com- 6 5 pressed tablets containing other drugs and plastics here- 22 87 inbefore enumerated was carried out with volatile organic solvents such as methylene chloride, ethyl acetate and ethylene dichloride. Although acetone is the solvent of The abeve data clearly Illustrates the effect of afietohe choice, it will be apparent to those skilled in the art that treatment 011 the release of the drug from the Plashe any solvent or mixture of solvents can be used in the presrier. With an untr at ta p i lly all Of the drug ent method provided it is volatile at reasonable operating is released within 30 minutes. fter actone tre conditions and is a solvent for the particular plastic ema good initial release of the drug occurs which gives the l d as h carrier for th d dosage level necessary for the desired therapeutic effect. I l i After this initial dose, the liberation of the drug slows 1 Th h d f prolonging h release f a d f down to a more uniform pace over the next several hours. a compressed mixture f drug and an inert water l Here g the Plashe Phh afiihere t0 eaehpther more ble, non-toxic, non-brittle, synthetic polymer having a tenacwusly to prevent dlsmtegratwn and provlde gradual glass point of at least 105 P. which comprises exposing release of the drug. said mixture to the vapors of a 'volatile organic solvent for Exam le 1 0 said polymer in a confined space for a period of time sufp ficient to result softening the surface of said polymer The following for-mualtion was compressed into tablets and thus fuse The lhdlvldual P y Pameles throughout wherein all ingredients and amounts are given on a p the mixture into a foraminous structure to further embed tablet basis: the drug thereinlMg 2. The product produced by the method of claim 1. Hexocyclium th l lfate 100 3. A method as claimed in claim 1 wherein the polymer Carbowax 0 117 is a co-polymer of methylacrylate and methylmethacrylate. Methylacrylateqnethylmethacrylate 1 117 4. A method as claimed in claim 3 wherein the solvent Talc 13,3 employed is selected from the group consisting of acetone, Magnesium stearate 6,6 methylene chloride, ethyl acetate, ethylene dichloride and toluene. The tablets were thereafter subjected to acetone vapors 5. The method of prolonging the release of a drug in a closed container for 3 hours at a temperature of 25 from an inert, water insoluble, non-toxic, non-brittle, syn- C. The tablets were then air dried and the release of the thetic polymer carrier having a glass point of at least 105' drug from the tablets was determined in vitro by contact- F. which comprises exposing a compressed tablet of said drug and said carrier to acetone vapors in a confined space for a sufficient period of time to soften and coalesce the individual particles in said carrier into a foraminous structure throughout the tablet to further embed the drug therein.
6. The product produced by the method of claim 5.
7. A method as claimed in claim 5 wherein the drug is selected from the group consisting of hexocyclium methylsulfate, methamphetamine hydrochloride, nicotinic acid, phenobarbital sodium and sodium paraminobenzoate.
8. A method as claimed in claim 5 wherein the polymer carrier is selected from the group consisting of polyethylene, polyvinylacetate, polymethylmethacrylate and methylacrylate-methylmethacrylate co-polymers.
9. The method of prolonging the release of methamphetamine hydrochloride from a non-toxic, inert, water insoluble, non-brittle, synthetic methylacrylate-methylmethacrylate co-polymer which comprises exposing a compressed tablet of said hydrochloride and said c0- polymer to acetone vapors in a vacuum chamber for about 5 hours at a temperature of about 30 C. and a pressure of about 240 millimeters of mercury to fuse the individual particles of co-polymer throughout the tablet into a foraminous structure to further embed the drug therein.
10. A method of prolonging the release of hexocyclium methylsulfate from a non-toxic, inert, water insoluble, non-brittle, synthetic methylacrylatemethylmethacrylate co-polymer which comprises exposing a compressed tablet of said sulfate and said co-polymer to acetone vapors in a closed container for about 24 hours at room temperature to fuse the individual particles of co-polymer throughout the tablet into a foraminous structure to further embed the drug therein.
'11. The method of treating the human body which comprises administering to a human host the product produced by the method of claim 5, said product being 3 adapted to release an efiective amount of drug gradually over a period of time during which the said product is present in the body.
References Cited in the file of this patent UNITED STATES PATENTS Re. 24,090 Diamond Nov. 15, 1955 312,041 Upjohn Feb. 10, 1885 2,149,005 Bockmiihl et a1 Feb. 28, 1939 2,385,920 Jenkins Oct. 2, 1945 2,478,182 Consolazio Aug. 9, 1949 2,707,201 Fernald et al. Apr. 26, 1955 2,719,093 -Voris Sept. 27, 1955 2,806,256 Smith-Johannsen Sept. 17, 1957 2,877,159 Lachman et a1 Mar. 10, 1959 2,894,289 Harper et al. July 14, 1959 2,928,769 Gaunt Mar. 15, 1960 2,928,771 Gaunt Mar. 15, 1960 2,955,982 Moeller et al. Oct. 11, 1960 2,987,455 Levesque June 6, 1961 FOREIGN PATENTS 548,310 Canada Nov. 5, 1957 665,073 Great Britain Jan. 16, 1952 OTHER REFERENCES Kennon: Dissertation Abstracts, vol. 16, No. 10, page 1889, December 1956, publication No. 18,412, Interaction Studies of Cationic Drugs With Anionic Poly Electriolytes, 103 pages, $1.50, Mic. 56-3004, University of Wisconsin, 1956.
Dragstedt: J.A.M.A., vol. 168, No. 12, Nov. 22, 1958, pp. 1652-1655.
Doerr et al.: Tablet Coatings: Cellulose High Polymers, I.A.Ph.A. Sci. ed. 43 (7), pp. 433-436, July 1954.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US312041 *||Feb 10, 1885||Process of making pills|
|US2149005 *||Nov 3, 1936||Feb 28, 1939||Winthrop Chem Co Inc||Shaped medicinal preparation|
|US2385920 *||Dec 19, 1941||Oct 2, 1945||Pittsburgh Plate Glass Co||Plasticization of plastics|
|US2478182 *||Jan 16, 1945||Aug 9, 1949||William V Consolazio||Sodium chloride tablet|
|US2707201 *||May 5, 1951||Apr 26, 1955||Richardson Co||Porous storage battery separator and method of making|
|US2719093 *||Jun 3, 1952||Sep 27, 1955||William H Voris||Methods of applying plastic coatings|
|US2806256 *||Jun 25, 1954||Sep 17, 1957||S J Chemical Company||Method of making microporous film|
|US2877159 *||Apr 26, 1957||Mar 10, 1959||Ciba Pharm Prod Inc||Method for preparing tablet granulations|
|US2894289 *||Mar 1, 1956||Jul 14, 1959||Dow Chemical Co||Method of making permeselective membranes|
|US2928769 *||Jul 22, 1957||Mar 15, 1960||Strong Cobb And Company Inc||Production of controlled release medicaments|
|US2928771 *||May 29, 1959||Mar 15, 1960||Strong Cobb And Company Inc||Production of orally administrable controlled release medicaments|
|US2955982 *||Oct 22, 1957||Oct 11, 1960||Parmelee Pharmaceutical Compan||Continuous process for internally reinforcing salt tablets|
|US2987455 *||Aug 7, 1956||Jun 6, 1961||Rodney G Hoff||Method and apparatus for reactor safety control|
|USRE24090 *||Nov 15, 1955||Impregnated salt tablet|
|CA548310A *||Nov 5, 1957||M. O. Honey Eric||Diaphragms for use in ion exchange processes|
|GB665073A *||Title not available|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US3138544 *||May 3, 1961||Jun 23, 1964||British Drug Houses Canada Ltd||Microbial sensitivity testing device|
|US3198700 *||May 29, 1961||Aug 3, 1965||Blessings Inc||Sedative tablet and method for producing the same|
|US3247066 *||Sep 12, 1962||Apr 19, 1966||Parke Davis & Co||Controlled release dosage form containing water-swellable beadlet|
|US3325365 *||Apr 2, 1963||Jun 13, 1967||Ciba Geigy Corp||Enteric composition for tablet compression coating|
|US3432592 *||Aug 28, 1963||Mar 11, 1969||Ciba Geigy Corp||Injection-moulded oral medicament in solid form|
|US3440320 *||Oct 11, 1966||Apr 22, 1969||Mortimer D Sackler||Chelated suppository and method of using same|
|US3453360 *||Apr 27, 1966||Jul 1, 1969||Abbott Lab||Universally useful stock material for manufacturing plastic dosage units by compression tableting processes|
|US3927206 *||Jul 12, 1974||Dec 16, 1975||Hydrophilics Int Inc||Copolymer containing medicaments|
|US3995632 *||Sep 30, 1974||Dec 7, 1976||Alza Corporation||Osmotic dispenser|
|US4547359 *||Mar 21, 1984||Oct 15, 1985||Boehringer Ingelheim Kg||Divisible pharmaceutical tablet with delayed active ingredient release|
|US4595587 *||Jul 3, 1985||Jun 17, 1986||Boehringer Ingelheim Kg||Divisible pharmaceutical tablet with delayed active ingredient release|
|US4704284 *||Aug 12, 1982||Nov 3, 1987||Pfizer Inc.||Long-acting matrix tablet formulations|
|US4851231 *||Mar 16, 1987||Jul 25, 1989||Alza Corporation||System for delivering drug in selected environment of use|
|US4851232 *||Jun 8, 1987||Jul 25, 1989||Alza Corporation||Drug delivery system with means for obtaining desirable in vivo release rate pattern|
|US4863744 *||Mar 16, 1987||Sep 5, 1989||Alza Corporation||Intestine drug delivery|
|US5011694 *||Aug 1, 1989||Apr 30, 1991||Rohm Gmbh||Pharmaceutical dosage unit forms with delayed release|
|US5153002 *||Aug 23, 1991||Oct 6, 1992||University Of Montreal||Biocompatible gradient controlled release implant|
|US5603956 *||Jun 16, 1994||Feb 18, 1997||Labopharm Inc.||Cross-linked enzymatically controlled drug release|
|US5616343 *||Mar 25, 1993||Apr 1, 1997||Labopharm, Inc.||Cross-linked amylose as a binder/disintegrant in tablets|
|US5807575 *||Feb 14, 1997||Sep 15, 1998||Rougier Inc.||Manufacture of cross-linked amylose useful as a excipient for control release of active compounds|
|US6607748||Jun 29, 2000||Aug 19, 2003||Vincent Lenaerts||Cross-linked high amylose starch for use in controlled-release pharmaceutical formulations and processes for its manufacture|
|US7829120||Sep 11, 2006||Nov 9, 2010||Labopharm Inc.||Trazodone composition for once a day administration|
|US7846477 *||Oct 9, 2003||Dec 7, 2010||Abbott Gmbh & Co. Kg||Method for producing solid galenic formulations using a crosslinked non-thermoplastic carrier|
|US7890171 *||Apr 20, 2007||Feb 15, 2011||Cardiac Pacemakers, Inc.||Sensors having protective eluting coating and method therefor|
|US7988998||Apr 22, 2005||Aug 2, 2011||Labopharm Inc.||Sustained-release tramadol formulations with 24-hour efficacy|
|US8131364||Jan 4, 2011||Mar 6, 2012||Cardiac Pacemakers, Inc.||Sensors having protective eluting coating and method therefor|
|US8298565||Jul 14, 2006||Oct 30, 2012||Micell Technologies, Inc.||Polymer coatings containing drug powder of controlled morphology|
|US8414919||Oct 15, 2010||Apr 9, 2013||Angelini Labopharm, Llc||Sustained drug release composition|
|US8487002||Apr 22, 2005||Jul 16, 2013||Paladin Labs Inc.||Controlled-release compositions|
|US8636767||Oct 2, 2007||Jan 28, 2014||Micell Technologies, Inc.||Surgical sutures having increased strength|
|US8758429||Sep 6, 2012||Jun 24, 2014||Micell Technologies, Inc.||Polymer coatings containing drug powder of controlled morphology|
|US8795723||Sep 11, 2006||Aug 5, 2014||Angelini Pharma Inc.||Sustained drug release compositions|
|US8795762||Mar 26, 2010||Aug 5, 2014||Battelle Memorial Institute||System and method for enhanced electrostatic deposition and surface coatings|
|US8834913||Dec 28, 2009||Sep 16, 2014||Battelle Memorial Institute||Medical implants and methods of making medical implants|
|US8852625||Apr 26, 2007||Oct 7, 2014||Micell Technologies, Inc.||Coatings containing multiple drugs|
|US8865688||Oct 2, 2009||Oct 21, 2014||Dr. Falk Pharma Gmbh||Compositions and methods for treatment of bowel diseases with granulated mesalamine|
|US8900651||Dec 4, 2008||Dec 2, 2014||Micell Technologies, Inc.||Polymer films for medical device coating|
|US8911778||Aug 3, 2012||Dec 16, 2014||Dr. Falk Pharma Gmbh||Pellet formulation for the treatment of the intestinal tract|
|US8940328||Mar 8, 2013||Jan 27, 2015||Dr. Falk Pharma Gmbh||Pellet formulation for the treatment of the intestinal tract|
|US8956647||Jul 26, 2013||Feb 17, 2015||Dr. Falk Pharma Gmbh||Pellet formulation for the treatment of the intestinal tract|
|US8962019||Oct 15, 2010||Feb 24, 2015||Angelini Pharma, Inc.||Sustained drug release composition|
|US9415142||Aug 29, 2014||Aug 16, 2016||Micell Technologies, Inc.||Coatings containing multiple drugs|
|US9433516||Apr 16, 2010||Sep 6, 2016||Micell Technologies, Inc.||Stents having controlled elution|
|US9439866||Sep 28, 2010||Sep 13, 2016||Angelini Pharma, Inc.||Trazodone composition for once a day administration|
|US9486338||Dec 9, 2015||Nov 8, 2016||Micell Technologies, Inc.||Stents having controlled elution|
|US9486431||Jul 16, 2009||Nov 8, 2016||Micell Technologies, Inc.||Drug delivery medical device|
|US9510856||Jul 16, 2010||Dec 6, 2016||Micell Technologies, Inc.||Drug delivery medical device|
|US9539593||Oct 23, 2007||Jan 10, 2017||Micell Technologies, Inc.||Holder for electrically charging a substrate during coating|
|US9636309||Sep 9, 2011||May 2, 2017||Micell Technologies, Inc.||Macrolide dosage forms|
|US9687864||Jun 20, 2014||Jun 27, 2017||Battelle Memorial Institute||System and method for enhanced electrostatic deposition and surface coatings|
|US20060172006 *||Oct 6, 2004||Aug 3, 2006||Vincent Lenaerts||Sustained-release tramadol formulations with 24-hour clinical efficacy|
|US20060240107 *||Apr 22, 2005||Oct 26, 2006||Vincent Lenaerts||Controlled-release compositions|
|US20060257470 *||Oct 9, 2003||Nov 16, 2006||Abbott Gmbh & Co. Kg||Method for producing solid galenic formulations using a crosslinked non-thermoplastic carrier|
|US20070003618 *||Apr 22, 2005||Jan 4, 2007||Vincent Lenaerts||Sustained-release tramadol formulations with 24-hour efficacy|
|US20070009564 *||Jun 22, 2005||Jan 11, 2007||Mcclain James B||Drug/polymer composite materials and methods of making the same|
|US20070128269 *||Sep 11, 2006||Jun 7, 2007||Sonia Gervais||Sustained drug release compositions|
|US20070128275 *||Sep 11, 2006||Jun 7, 2007||Sonia Gervais||Trazodone composition for once a day administration|
|US20070191921 *||Apr 20, 2007||Aug 16, 2007||Cardiac Pacemakers, Inc.||Sensors having protective eluting coating and method therefor|
|US20080095919 *||Oct 23, 2007||Apr 24, 2008||Mcclain James B||Holder For Electrically Charging A Substrate During Coating|
|US20090047345 *||Apr 22, 2005||Feb 19, 2009||Vincent Lenaerts||Sustained-release tramadol formulations with 24-hour efficacy|
|US20090062909 *||Jul 14, 2006||Mar 5, 2009||Micell Technologies, Inc.||Stent with polymer coating containing amorphous rapamycin|
|US20090123515 *||Jul 14, 2006||May 14, 2009||Doug Taylor||Polymer coatings containing drug powder of controlled morphology|
|US20090186069 *||Apr 26, 2007||Jul 23, 2009||Micell Technologies, Inc.||Coatings Containing Multiple Drugs|
|US20090292351 *||Apr 17, 2009||Nov 26, 2009||Micell Technologies, Inc.||Stents having bioabsorbable layers|
|US20100015200 *||Jul 16, 2009||Jan 21, 2010||Micell Technologies, Inc.||Drug Delivery Medical Device|
|US20100086588 *||Oct 2, 2009||Apr 8, 2010||Salix Pharmaceuticals, Ltd.||Compositions and methods for treatment of bowel diseases with granulated mesalamine|
|US20100151022 *||Apr 22, 2005||Jun 17, 2010||Vincent Lenaerts||Controlled-release compositions|
|US20100211164 *||Apr 17, 2008||Aug 19, 2010||Mcclain James B||Stents having biodegradable layers|
|US20100228348 *||May 23, 2008||Sep 9, 2010||Micell Technologies, Inc.||Polymer Films for Medical Device Coating|
|US20100239635 *||Mar 23, 2010||Sep 23, 2010||Micell Technologies, Inc.||Drug delivery medical device|
|US20100241220 *||Mar 22, 2010||Sep 23, 2010||Mcclain James B||Peripheral Stents Having Layers|
|US20100256746 *||Mar 23, 2010||Oct 7, 2010||Micell Technologies, Inc.||Biodegradable polymers|
|US20100256748 *||Mar 31, 2010||Oct 7, 2010||Micell Technologies, Inc.||Coated stents|
|US20100272778 *||Apr 16, 2010||Oct 28, 2010||Micell Technologies, Inc.||Stents having controlled elution|
|US20100298928 *||Oct 17, 2008||Nov 25, 2010||Micell Technologies, Inc.||Drug Coated Stents|
|US20110015205 *||Sep 28, 2010||Jan 20, 2011||Sonia Gervais||Trazodone Composition for Once a Day Administration|
|US20110021535 *||Sep 28, 2010||Jan 27, 2011||Sonia Gervais||Trazodone Composition for Once a Day Administration|
|US20110027370 *||Oct 15, 2010||Feb 3, 2011||Sonia Gervais||Sustained Drug Release Composition|
|US20110033537 *||Oct 15, 2010||Feb 10, 2011||Sonia Gervais||Sustained Drug Release Composition|
|US20110159069 *||Dec 28, 2009||Jun 30, 2011||Shaw Wendy J||Medical Implants and Methods of Making Medical Implants|
|US20110238161 *||Mar 26, 2010||Sep 29, 2011||Battelle Memorial Institute||System and method for enhanced electrostatic deposition and surface coatings|
|EP0355470A2 *||Jul 28, 1989||Feb 28, 1990||Röhm Gmbh||Pharmaceutical form with sustained release, and process for its preparation|
|EP0355470A3 *||Jul 28, 1989||Mar 28, 1990||Rohm Gmbh||Pharmaceutical form with sustained release, and process for its preparation|
|WO2007002238A3 *||Jun 21, 2006||May 10, 2007||Micell Technologies Inc||Drug/polymer composite materials and methods of making the same|
|U.S. Classification||424/419, 514/356, 514/567, 514/654, 514/270|
|International Classification||A61K9/20, A61K9/22|
|Cooperative Classification||A61K9/2095, A61K9/2027|
|European Classification||A61K9/20P, A61K9/20H6B|