|Publication number||US2987445 A|
|Publication date||Jun 6, 1961|
|Filing date||Oct 10, 1958|
|Priority date||Oct 10, 1958|
|Publication number||US 2987445 A, US 2987445A, US-A-2987445, US2987445 A, US2987445A|
|Inventors||Charles L Levesque|
|Original Assignee||Rohm & Haas|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (6), Referenced by (124), Classifications (18)|
|External Links: USPTO, USPTO Assignment, Espacenet|
June 6, 1961 c. L. LEVESQUE DRUG COMPOSITION 2 Sheets-Sheet 1 Filed Oct. 10, 1958 June 6, 1961 c. 'L. LEVESQUE 2,987,445
DRUG COMPOSITION Filed Oct. 10, 1958 2 Sheets-Sheet 2 q- 0: DJ '0 l- LL 3 4 U) (I D N g l l l O O O O 00 (0 q N GBSVB IHH SFIHCI :IO .LNEIOHI-Id United States Patent 2,987,445 DRUG COMPOSITION v Charles L. Levesque, Philadelphia, Pa., assignor to Rohm & Haas Company, Philadelphia, Pa., a corporation of Delaware Filed Oct. 10, 1958, Ser. No. 766,496 14 Claims. (Cl. 167-82) This invention relates to a new drug composition and a method for the administration of drugs. More particularly, the invention relates to a new composition of a drug dispersed in plastic and suitable for oral ad ministration.
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 irritating to the gastro-intestinal tract and particularly to the stomach. Secondly, it may be destroyed in the stomach. Thirdly, it may be too readily absorbed with the consequent danger from toxic dosage, or it may be too readily excreted and pass out of the body before the therapeutic efiect can be realized.
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 eliective. In every instance the enteric coating is designed 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 medicaments is the type known as time-disintegration coatings. In these coatings a class of materials is used which is dissolved or disintegrated 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 difierences in the operation of the gastro-intestinal 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 the mechanism of the average individual.
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-intestinal fluids. The enzymes, fat-solubilizers and emulsifiers in these fliuds hasten the breaking-up or wearing-away of the coatings.
It is a principal object of the present invention therefore to provide an orally effective dosage form in which the drug will be slowly but uniformly released in the body.
Another object of the invention is to provide a dosage form which will release an effective amount of the drug within a short time after ingestion and which will continue to release the drug over an extended period of time.
A further object of the invention is to provide 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 be more readily appreciated by reference to the following description when considered in connection with the accompanying drawings wherein:
FIGURE 1 is a schematic drawing of a compressed tablet comprising a plastic carrier 19 in which is uniformly dispersed, particles of a solid drug 11.
FIGURE 2 is a schematic drawing showing the voids 12 from which the drug is physically leached from the plastic carrier 10 by the gastro-intestinal fluids upon ingestion.
FIGURE 3 is a schematic drawing of a completely leached tablet showing the plastic carrier 10 which remains intact and the cavities 13 from which the drug has been leached.
FIGURE 4 is a perspective view of a compressed tablet with parts broken away in cross-sectional showing the plastic carrier 10 and dispersed particles of drug 11. It should be noted that some of the drug particles actually touch each other as illustrated at 14 Whereas other particles of drug present on the surface of the plastic carrier as illustrated at 15.
FIGURE 5 is a graph showing the cumulative amount of drug released over a period of eight hours after ingestion.
In the accomplishment of the foregoing objects and in accordance with the practice of this invention there is now provided a combination of a drug and, if desired, a water-soluble excipient dispersed uniformly in a body of a non-toxic synthetic plastic material. When such a compostion comes into contact with an aqueous liquid the drug is leached out or difiused out of the plastic body. The amount of drug released in the early stages of the leaching out process is sufiicient 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 chemica 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, paraarnino benzoic acid, ephedrine, mannitol hexanitrate, amphetamine, erythromycin salts, penicillin salts, pentobarbital, phenobarbital, atropine, belladonna, theophylline, sex hormones, hydantoins, trimethadione, water-soluble vitamins such as B and C, benzazoline, toluidine blue 0 and related drugs are respresentative of the broad class of drugs which may be administered in this new composition form.
The plastics to which this invention pertains may be any synthetic resinous or polymeric material which is substantially inert to gastro-intenstinal 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 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, polyhexamethylene adipam ide and the like. The monomers employed to prepare the copolymers may be present in a ratio of from 60-40 to 40-60.
The polymers can be prepared by bulk, solution, suspension, or emulsion polymerization. It 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 below.
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 of this invention may be described as having discrete particles of a drug dispersed in a matrix ofa 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, but the drug is accessible to liquids and may be removed from the plastic body by a leaching or Washing action without materially afiecting the physical condition of the plastic body.
In order to be an eitective carrier for the drug the plastic may be permeable to the gastro-intestinal fluids to at least a small extent sufiicient to allow leaching out of most of the drug during the time that the plastic is retained by the average person. It should be noted that the degree of water permeability may be low and still be effective. For instance, polyethylene has a very low Water permeability, and yet it is satisfactory for use in this invention.
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, polyvinyl-pyrrolidone, inositol, lactose, mannitol, methocel, calcium chloride, pectin and the like.
The new composition 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 powder with the drug in crystalline or granular form and then subject the mixture to heat and pressure so that the plastic is converted into a solid body or mass having the drug dis persed therein. The plastic mass is then ground, shaved or otherwise comminuted into particles of a desired size. Particle size is an important aspect of the invention since the rate of diffusion or leaching out of a drug from a given plastic will be faster from a small particle than it will be from a large particle. It is possible by the use of selected proportions of particles having difierent sizes to arrive at any desired rate of diffusion or leaching out. 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, insoluble 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 crum 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 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 of this invention is preferably administered by grinding or otherwise comminuting the plastic mass having the drug embedded therein to a desired particle size or range of particle sizm and mixing, com bining or incorporating in a pharmaceutical cmer. The particles may be recombined with tableting adjuvants in the form of conventional pharmaceutical tablets.
In a preferred method of operation, the individual plastic particles, the drug, and water-soluble excipient may be fused by exposing the compressed tablets to acetone vapor until they become soft and pliable throughout. Upon drying the treated tablet, the plastic forms a network of continuous interstices throughout the tablet which resists disintegration during exposure to Water for a considerable length of time. Such acetone treatment may be carried out at room temperature in a closed container for a period or" about 24 hours but the process can be accelerated if desired by the use of heat and/ or vacuum as described in a copending application.
The following examples are presented order to provide specific embodiments of the invention in detail. It is not intended, however, that the examples should be a limitation on the invention in any way.
Example I About 50 parts by weight of paraamino benzoic acid and 50 parts by weight of polyethylene are mixed thoroughly and the mixture is pressed into sheets having a thickness between about 35 and 75 mils "(thousandths of an inch) by pressing in cauls at 220260 F.- and at an average pressure between 200 and 600 p.s.i. One sample 75 mils in thickness was cut into pieces 1 centimeter in length (393 mils) and 8 mils wide. Another sample 75 mils in thickness was cut into pieces 1 centimeter in length (393 mils) and 22 mils wide.
Excretion studies in humans using the described composition 8 mils wide and comparing to paraamino benzoic controls show that 2.1 times as long is required for excretion of 50% of the dose of paraamino benzoic acid from the composition as is required for excretion of 5 of the control dose of the same drug. This rate is substantially independent of the size of the dose.
With the composition 22 mils wide (by 75 x 393 mils) 2.8 to 3.0 times as long is required for excretion of 50% of the dose of paraamino benzoic acid therefrom as is required for excretion of 0% of the control dose. This finding bears out the theory that particle size is an important factor in the rate of release of the drug from the plastic; the rate of release being inversely proportional to the size of the particle.
The 8 mils material (by 75 x 393 mils) had approximately 2.75 times the surface area of the 22 mils material (by 75 x 393 mils) for an equal weight, and released about 3.1 times as much paraamino benzoic acid in water in six minutes as did the 22 mils material.
Example II Tablets are prepared according to the following directions, the amounts of each component being on a per tablet basis:
Mix the methamphetamine hydrochloride with the polyvinylpyrrolidone and mill through a hammermill using a 30-mesh screen. Charge this mix with the plastic, talc and magnesium stearate into a blender and blend well. Compress into tablets and fuse by heating or exposing said tablets to acetone vapor.
Example 111 75 mg. of a plastic composition consisting of polyethylene particles having 20% by weight of methamphetamine dispersed therein is placed in a small hard-gelatin capsule suitable for administration to a human host.
Example IV A mixture comprising methamphetamine and 90% granular polyethylene is ball milled and dried. The mixture is compression molded in sheets about 5 inches square and to varying thicknesses on a 6 x 6 Carver press (10,000 p.s.i. on 1% inch ram at 130 C. for 2 minutes). Similar samples were made in like manner using 20% methamphetamine with 80% polyethylene, and 40% methamphetamine with 60% polyethylene. In general it may be said that the release of drug out of these compositions is directly proportional to the concentration of drug and inversely proportional to the particle size of the material obtained by comminuting the aforementioned sheets.
Example V A mixture comprising 10% methamphetamine and 90% of a 1:1 copolymer of methylmethacry-late-methylacrylate is thoroughly blended and compressed on the Carver press (see Example IV) at 150 C. for 3 minutes.
6 Similar samples were made in like manner using 20% methamphetamine and of said copolymer, and 40% methamphetamine and 60% copolymer. The release of drug from particles obtained by comminuting the samples follows the general pattern stated in Example IV.
Example VI A rod was extruded from a 1 inch National Rubber Machinery Co. extruder at temperatures between 285 and 335 F. The material was a blend of 40% methamphetamine, 59% polyethylene and 1% stearic acid. This rod is cornminuted to small particle size and the product showed the same drug release as in Example IV.
Example VII Tablets are prepared according to the following directions by employing the amounts of the following ingredients on a per tablet basis:
' Mg. Methamphetamine hydrochloride 15.00 Poly-vinylpyrrolidone 14.00 Yellow lake dye 0.03 Talc 4.66 Methylacrylate-methylmethacrylate copolymer (80 mesh) 19.85 Methylacrylate-methylmethacrylate copolymer (30 mesh) 60.65 Magnesium stearate 2.47
A formulation was prepared employing the following components, the amounts of each component being on a per tablet basis:
Mg. Hexocyclium methylsulfate 50.0 Methylacrylate-methylmethacrylate copolymer (20 mesh) 48.4 Talc 5.2 Magnesium stearate 0.4
Thoroughly blend the plastic and hexocyclium methylsulfate. Then add the talc and magnesium stearate, blend for 45 minutes, compress into tablets and fuse the tablets by exposure to acetone vapor. The drug will be released gradually over an 8 to 12 hour period after a tablet is ingested.
Example IX Another formulation was prepared as shown below wherein all ingredients and amounts are on a per tablet basis:
The ingredients are all charged into a suitable blender and mixed well. The mixture is then passed through a 40-mesh screen and reblended followed by compression into tablets. The drug in this composition'will be released slowly over a period of 8 hours after oral administration of one tablet.
Example X Mg. Methamphetamine hydrochloride 15.0 Pentobarbital calcium 90.0 'Methylacrylate-methylmetbacrylate copolymer (80 mesh) 9.5 Calcium chloride 4.8 Talc 9.3 Magnesium stearate 4.6
Example X1 Tablets were prepared containing the following ingredients by weight Piperazine tartrate 209 Methylacrylate-methylmethacrylate copolymer (80 mesh) 104 Talc 12 Magnesium stearate 3 Blend all the ingredients and pass through a 40-mesh screen. Compress the mixture into slugs and grind the slugs first through a 4-mesh screen and then through a 20-mesh screen. Blend well and compress into tablets. The release pattern of these tablets is as shown in FIG- URE 5.
Example X 11 A tablet was prepared as described inExample XI containing the following amounts of each component listed.
Nicotinic acid 400 Methylacrylate-methylmethacrylate copolymer (80 mesh) 100 Talc 20 Magnesium stearate 5 Upon ingestion of such a tablet, the nicotinic acid is gradually released from the plastic over a period of 8 hours.
Example XIII By employing the procedure of Example XI, tablets were prepared containing the following ingredients in the amounts specified.
Phenobarbital sodium 72 Methylacrylate-methylmethacrylate copolymer (80-mesh) 72 Talc 5.7
Magnesium stearate 1.4
These tablets release the phenobarbital according to the pattern illustrated in FIGURE 5 when such tablets are orally ingested;
Example XIV The following components are mixed and compressed into tablets by methods previously described. The amounts given are on a per tablet basis:
1 Mg. Nicotinamide 20 Thiamine mononitrate 3 Pyridoxine hydrochloride 0.5 Calcium pantothenate 5 Sodium ascorbate 50 Vitamin B .002 Methylacrylate-methylmethacrylate copolymer mesh) Talc 2.8 Magnesium stearate 1.4
The vitamins in this formulation are slowly leached from the plastic carrier over an extended period of about 12 hours after a tablet is orally administered.
Other water-soluble excipients and other plastics heretofore enumerated may be substituted in the foregoing formulations with equally effective results as regards the release of the drug from the plastic carrier over an extended period of time.
This application is a continuation-in-part of my copcnding application Serial No. 533,504, filed September 9, 1955 now abandoned.
Others may practice this invention in any of the numerous ways which will be suggested to one skilled in the art upon a reading of this disclosure. All such practice of the invention is considered to be a part thereof provided it falls within the scope of the appended claims.
1. A composition in oral dosage form which comprises (a) -a porous plastic matrix which is substantially inert to gastro-intestinal fluids, said plastic being permeable to the water component of gastro-intestinal fluids to at least a small extent and being selected from the group consisting of crystalline polymers having a melting point of at least about 105 F. and amorphous polymers having a glass point of at least about 105 F. and (b) an amount of a water soluble drug suificient to give a. pharmacologic response upon ingestion and absorption, said drug being uniformly dispersed within the pores of said plastic matrix and said composition adapted to release an eifective amount of the drug gradually over a period of time during which the dosage form is present in the body.
2. A composition in tablet form which comprises (a) a porous plastic matrix which is substantially inert to gastro-intestinal fluids, said plastic being permeable to the water component of gastro-intcstinal fluids to at least a small extent and being selected from the group consisting of crystalline polymers having a melting point of at least about 105 F. and amorphous polymers having a glass point of at least about 105 F. and (b) 10 to parts by weight of a water soluble drug, said drug being uniformly dispersed Within the pores of said plastic matrix and said tablet adapted to release an effective amount of the drug gradually over a period of time during which the tablet is present in the body.
3. A tablet as claimed in claim 2 in which plastic particles and drug particles are blended and the resulting blend is compressed into tablets.
4. A tablet as claimed in claim 2 to which is added a water soluble excipient.
5. A tablet as claimed in claim 2 which comprises about 30 parts by weight of a water soluble drug and about 70 parts by weight of an amorphous polymer having :a glass point of at least about F.
6. A tablet as claimed in claim 2 which comprises from about 10 to 90 parts by weight of a water soluble drug and the plastic is a methylacrylate-methylmethacrylate copolymer, said copolymer being present in an amount of from about 90 to 7 parts by weight of the tablet.
7. A tablet as claimed in claim 2 which comprises about 50 parts by weight of a water soluble drug and 9 about 50 parts by weight of a methylacrylate-methylmethacrylate copolymer.
8. A tablet as claimed in claim 2 which comprises from about to 90 parts by weight of a water soluble drug and the plastic is polyethylene which is present in an amount of about 90 to 7 parts by weight of the tablet.
9. A tablet as claimed in claim 2 which comprises about 30 parts by weight of a water soluble drug and about 70 parts by weight of polyethylene.
10. A tablet as claimed in claim 2 in which the drug is methamphetamine.
11. A tablet as claimed in claim 2 hexocyclium methylsulfate.
12. The method of making an oral dosage form which comprises blending (a) from about 10 to 90 parts by weight of a finely divided water soluble drug with (b) from about 90 to 10 parts by weight of a plastic which is substantially inert to gastro-intestinal fluids but permeable to the water component of gastro-intestinal fluids to at least a small extent, said plastic being selected from the group consisting of crystalline polymers having a melting point of at least about 105 F. and amorphous polymers having a glass point of at least about 105 F. and compressing said blended mixture into a tablet having said drug uniformly dispersed therein.
13. The method of treating the human body which comprises administering to a human host a tablet comprising (a) a porous plastic matrix which is substantially inter to gastro-intestinal fluids, said plastic being permeable to the water component of said fluids to at least a small extent and being selected from the group consisting of crystalline polymers having a melting point of at least about 105 F. and amorphous polymers having a glass point of at least about 105 F. and (b) an amount of a water soluble drug suflicient to give a pharmacologic response upon ingestion and absorption, said drug being in which the drug is 10 l uniformly dispersed within the pores of said plastic matrix and said tablet adapted to release an effective amount of the drug gradually over a period of time during which the tablet is present in the body.
14. The method as claimed in claim 13 in which the tablet adminstered comprises from about 10 to parts by weight of a water soluble drug uniformly dispersed in the pores of a methylacrylate-methylmethacrylate copolymer.
References Cited in the file of this patent UNITED STATES PATENTS 2,478,182 Consolazio Aug. 9, 1949 2,702,264 Klaui Feb. 15, 1955 2,805,977 Robinson Sept. 10, 1957 2,820,741 Endicott Ian. 21, 1958 FOREIGN PATENTS 217,287 Australia Sept. 16, 1958 630,439 Great Britain Oct. 13, 1949 OTHER REFERENCES Journal of the American Pharmaceutical Assoc, October 1954, pages 591-592.
The Merck Index, 6th Edition, 1952, pages 314-315.
Physicians Desk Reference, 1955, Ninth Ed., page 524.
Modern Plastics Encyclopedia Issue, September 1954, published by Breskin Publications, Inc., 575 Madison Ave,. N.Y. 22, N.Y., pp. 1, 805, 806, 807, 808, 809.
Micciche: Preparation of Orally Administered Medicaments With Predictable Retarded Effect, in Pharmaceutical Chemical Bulletin, Milan, Italy, vol. 94, pp. 485-493 (1955), in Italian: abstracted in English in Chem. Abstracts, vol. 50, No. 7, #5242g, April 10, 1956, Oflicial Patent Ofiice translation from the Italian article, FHB-6-20-60, pp. 1-16.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US2478182 *||Jan 16, 1945||Aug 9, 1949||William V Consolazio||Sodium chloride tablet|
|US2702264 *||Mar 8, 1951||Feb 15, 1955||Hoffmann La Roche||Enteric coated tablet|
|US2805977 *||Jan 4, 1955||Sep 10, 1957||Smith Kline French Lab||Sustained release pharmaceutical preparation|
|US2820741 *||Apr 29, 1954||Jan 21, 1958||Abbott Lab||Aluminum aspirin granulation and method for making|
|AU217287B *||Title not available|
|GB630439A *||Title not available|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US3039933 *||Oct 7, 1957||Jun 19, 1962||Premo Pharmaceutical Lab Inc||Ethyl cellulose-polyethylene glycol tablet matrix|
|US3048526 *||Aug 4, 1958||Aug 7, 1962||Wander Company||Medicinal tablet|
|US3062720 *||May 20, 1959||Nov 6, 1962||Philips Roxane||Sustained release pharmaceutical tablet|
|US3070509 *||Dec 15, 1959||Dec 25, 1962||Roehm & Haas Gmbh||Process for coating medicaments|
|US3071476 *||May 12, 1960||Jan 1, 1963||Allan J Werft||Chewing device|
|US3073748 *||Nov 17, 1961||Jan 15, 1963||Tanabe Seiyaku Co||Coated medicaments|
|US3074852 *||Jun 6, 1960||Jan 22, 1963||American Home Prod||Pharmaceuticals with delayed release|
|US3096248 *||Apr 6, 1959||Jul 2, 1963||Rexall Drug & Chemical Company||Method of making an encapsulated tablet|
|US3101293 *||Apr 28, 1961||Aug 20, 1963||Strong Cobb Arner Inc||Controlled release compositions and their preparation|
|US3109775 *||Jan 31, 1961||Nov 5, 1963||Key Pharma||Theophylline-noscapine sustained release composition for treatment of asthma|
|US3132067 *||Aug 15, 1960||May 5, 1964||Barth Hans||Metal phosphide compositions and a process for their production|
|US3133863 *||Mar 10, 1961||May 19, 1964||Strong Cobb Arner Inc||Sustained release therapeutic tablet compositions comprising organic solvent-gelled gums|
|US3136695 *||Mar 10, 1961||Jun 9, 1964||Strong Cobb Arner Inc||Anhydrous thixotropic gel sustained release therapeutic compositions and method of preparation|
|US3146169 *||Jun 8, 1962||Aug 25, 1964||Burroughs Wellcome Co||Pharmaceutical formulations and their manufacture|
|US3235466 *||Dec 13, 1960||Feb 15, 1966||Atomic Energy Authority Uk||Fuel elements for nuclear reactors|
|US3276949 *||May 7, 1963||Oct 4, 1966||Olin Mathieson||Tablets comprising calcium hypochlorite and sodium sulfate and method of preparation|
|US3279996 *||Aug 28, 1962||Oct 18, 1966||Folkman Moses Judah||Polysiloxane carrier for controlled release of drugs and other agents|
|US3358687 *||Dec 6, 1965||Dec 19, 1967||Sterling Drug Inc||Suppositories|
|US3391477 *||Oct 22, 1965||Jul 9, 1968||Abbott Lab||Educational model of pharmaceutical device|
|US3432592 *||Aug 28, 1963||Mar 11, 1969||Ciba Geigy Corp||Injection-moulded oral medicament in solid form|
|US3453360 *||Apr 27, 1966||Jul 1, 1969||Abbott Lab||Universally useful stock material for manufacturing plastic dosage units by compression tableting processes|
|US3487138 *||Nov 23, 1966||Dec 30, 1969||Merck & Co Inc||Process for preparing a delayed release medicinal tablet|
|US3499445 *||Aug 16, 1966||Mar 10, 1970||Phytogen Prod Inc||Animal husbandry|
|US3916898 *||Jul 10, 1970||Nov 4, 1975||Searle & Co||Administration of medicaments and the like|
|US3920806 *||May 4, 1973||Nov 18, 1975||Merck & Co Inc||Growth promoting subcutaneous compositions|
|US4013784 *||Oct 2, 1974||Mar 22, 1977||Peter Speiser||Delayed release pharmaceutical preparations|
|US4059686 *||Sep 22, 1975||Nov 22, 1977||Nippon Kayaku Kabushiki Kaisha||Pharmaceutical preparation for oral cavity administration|
|US4115590 *||Jan 28, 1970||Sep 19, 1978||Ethyl Corporation||Binuclear phenols for reducing plasma lipid levels|
|US4217898 *||Oct 23, 1978||Aug 19, 1980||Alza Corporation||System with microporous reservoir having surface for diffusional delivery of agent|
|US4351825 *||Jan 14, 1980||Sep 28, 1982||Orion-Yhtyma Oy||Process for the preparation of tablets with retarded liberation of the active agent is predetermined|
|US4421742 *||Mar 4, 1981||Dec 20, 1983||Dr. Werner Freyberg Chemische Fabrik Delitia Nachf.||Phosphine producing pesticide and method of manufacture therefor|
|US4499066 *||Jul 30, 1982||Feb 12, 1985||Farmitalia Carlo Erba S.P.A.||Pharmaceutical sustained-release compositions|
|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|
|US4600584 *||Sep 7, 1983||Jul 15, 1986||Dr. Werner Freyberg Chemische Fabrik Delitia Nachf||Phosphine producing hydrolyzable metal phosphide and use thereof|
|US4605550 *||Jun 5, 1984||Aug 12, 1986||A. H. Robins Company, Inc.||Delayed release formulations and processes for making them|
|US4666704 *||May 24, 1985||May 19, 1987||International Minerals & Chemical Corp.||Controlled release delivery system for macromolecules|
|US4666705 *||Jun 3, 1985||May 19, 1987||E. R. Squibb & Sons, Inc.||Controlled release formulation|
|US4687660 *||Aug 15, 1984||Aug 18, 1987||Burroughs Wellcome Co.||Pharmaceutical delivery system|
|US4704284 *||Aug 12, 1982||Nov 3, 1987||Pfizer Inc.||Long-acting matrix tablet formulations|
|US4720384 *||Aug 21, 1986||Jan 19, 1988||E. I. Du Pont De Nemours And Company||Manufacture of hollow fine tubular drug delivery systems|
|US4725387 *||Jan 30, 1985||Feb 16, 1988||Kabushiki Kaisha Hayashibara Seitbutsu Kagaku Kenkyujo||Process of shaping anhydrous crystals of maltitol and the whole crystalline hydrogenated starch hydrolysate mixture solid containing the crystals|
|US4803076 *||Sep 4, 1986||Feb 7, 1989||Pfizer Inc.||Controlled release device for an active substance|
|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|
|US4960765 *||Jun 26, 1989||Oct 2, 1990||Farmaceutisk Laboratorium Ferring A/S||Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration|
|US4975270 *||Apr 21, 1987||Dec 4, 1990||Nabisco Brands, Inc.||Elastomer encased active ingredients|
|US4980173 *||Jun 26, 1989||Dec 25, 1990||Farmaceutisk Laboratorium Ferring A/S||Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration|
|US5011694 *||Aug 1, 1989||Apr 30, 1991||Rohm Gmbh||Pharmaceutical dosage unit forms with delayed release|
|US5013727 *||Jun 26, 1989||May 7, 1991||Farmaceutisk Laboratorium Ferring A/S||Pharmaceutical composition and method for the treatment of colitis ulcerosa and Crohn's disease by oral administration|
|US5041431 *||Jun 26, 1989||Aug 20, 1991||Farmaceutisk Laboratorium Ferring A/S|
|US5137669 *||May 24, 1991||Aug 11, 1992||Endocon, Inc.||Manufacture of partially fused peptide pellet|
|US5153002 *||Aug 23, 1991||Oct 6, 1992||University Of Montreal||Biocompatible gradient controlled release implant|
|US5510115 *||Dec 8, 1994||Apr 23, 1996||Baxter Travenol Laboratories, Inc.||Method and composition for administration of beneficial agent by controlled dissolution|
|US5552159 *||Sep 23, 1993||Sep 3, 1996||Basf Aktiengesellschaft||Solid depot drug form|
|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|
|US5853758 *||Jul 10, 1996||Dec 29, 1998||Pfizer Inc.||Preparation of tablets of increased strength|
|US6210716||Feb 26, 1999||Apr 3, 2001||Andrx Pharmaceuticals, Inc.||Controlled release bupropion formulation|
|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|
|US6893660||Nov 21, 2002||May 17, 2005||Andrx Pharmaceuticals, Inc.||Stable pharmaceutical compositions without a stabilizer|
|US6905708||May 9, 2003||Jun 14, 2005||Andrx Pharmaceuticals, Inc.||Controlled release oral dosage form|
|US7771750||Mar 1, 2005||Aug 10, 2010||Andrx Pharmaceuticals, Llc||Controlled release oral dosage form|
|US7829120||Sep 11, 2006||Nov 9, 2010||Labopharm Inc.||Trazodone composition for once a day administration|
|US7988998||Apr 22, 2005||Aug 2, 2011||Labopharm Inc.||Sustained-release tramadol formulations with 24-hour efficacy|
|US8414919||Oct 15, 2010||Apr 9, 2013||Angelini Labopharm, Llc||Sustained drug release composition|
|US8431150||Feb 6, 2006||Apr 30, 2013||Wm. Wrigley Jr. Company||Breath freshening confectionery products and methods of making and using same|
|US8487002||Apr 22, 2005||Jul 16, 2013||Paladin Labs Inc.||Controlled-release compositions|
|US8501227||Jan 3, 2005||Aug 6, 2013||Andrx Pharmaceuticals, Llc||Stable pharmaceutical compositions without a stabilizer|
|US8545880||Feb 8, 2002||Oct 1, 2013||Andrx Pharmaceuticals, Llc||Controlled release oral dosage form|
|US8557323||Nov 15, 2012||Oct 15, 2013||Wm. Wrigley Jr. Company||Breath freshening confectionery products and methods of making and using same|
|US8722086||Mar 7, 2008||May 13, 2014||Gruenenthal Gmbh||Dosage form with impeded abuse|
|US8747898||Jul 14, 2010||Jun 10, 2014||Andrx Pharmaceuticals, Llc||Controlled release oral dosage form|
|US8795723||Sep 11, 2006||Aug 5, 2014||Angelini Pharma Inc.||Sustained drug release compositions|
|US8865688||Oct 2, 2009||Oct 21, 2014||Dr. Falk Pharma Gmbh||Compositions and methods for treatment of bowel diseases with granulated mesalamine|
|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|
|US9161917||Nov 1, 2010||Oct 20, 2015||Grünenthal GmbH||Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet|
|US9439866||Sep 28, 2010||Sep 13, 2016||Angelini Pharma, Inc.||Trazodone composition for once a day administration|
|US9629807||Apr 19, 2016||Apr 25, 2017||Grünenthal GmbH||Abuse-proofed dosage form|
|US9636303||Sep 1, 2011||May 2, 2017||Gruenenthal Gmbh||Tamper resistant dosage form comprising an anionic polymer|
|US9655853||May 27, 2016||May 23, 2017||Grünenthal GmbH||Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer|
|US9675610||Aug 24, 2016||Jun 13, 2017||Grünenthal GmbH||Abuse-proofed dosage form|
|US9737490||May 27, 2014||Aug 22, 2017||Grünenthal GmbH||Tamper resistant dosage form with bimodal release profile|
|US9750701||Dec 11, 2015||Sep 5, 2017||Grünenthal GmbH||Pharmaceutical dosage form|
|US20030161874 *||Feb 8, 2002||Aug 28, 2003||Boyong Li||Controlled release oral dosage form|
|US20030198683 *||May 9, 2003||Oct 23, 2003||Boyong Li||Controlled release oral dosage form|
|US20040101556 *||Nov 21, 2002||May 27, 2004||Boyong Li||Stable pharmaceutical compositions without a stabilizer|
|US20050142195 *||Jan 3, 2005||Jun 30, 2005||Boyong Li||Stable pharmaceutical compositions without a stabilizer|
|US20050147678 *||Mar 1, 2005||Jul 7, 2005||Boyong Li||Controlled release oral dosage form|
|US20060172006 *||Oct 6, 2004||Aug 3, 2006||Vincent Lenaerts||Sustained-release tramadol formulations with 24-hour clinical efficacy|
|US20060193909 *||Feb 6, 2006||Aug 31, 2006||Stawski Barbara Z||Breath freshening pressed tablets and methods of making and using same|
|US20060193914 *||Feb 6, 2006||Aug 31, 2006||Judy Ashworth||Crush resistant delayed-release dosage forms|
|US20060240107 *||Apr 22, 2005||Oct 26, 2006||Vincent Lenaerts||Controlled-release compositions|
|US20070003618 *||Apr 22, 2005||Jan 4, 2007||Vincent Lenaerts||Sustained-release tramadol formulations with 24-hour efficacy|
|US20070054014 *||Feb 6, 2006||Mar 8, 2007||Stawski Barbara Z||Breath freshening confectionery products and methods of making and using 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|
|US20070166430 *||Oct 19, 2006||Jul 19, 2007||Stawski Barbara Z||Breath freshening confectionery products and methods of making and using same|
|US20090047345 *||Apr 22, 2005||Feb 19, 2009||Vincent Lenaerts||Sustained-release tramadol formulations with 24-hour efficacy|
|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|
|US20100278926 *||Jul 14, 2010||Nov 4, 2010||Boyong Li||Controlled Release Oral Dosage Form|
|US20110015205 *||Sep 28, 2010||Jan 20, 2011||Sonia Gervais||Trazodone Composition for Once a Day Administration|
|US20110020451 *||Jul 21, 2010||Jan 27, 2011||Grunenthal Gmbh||Tamper-resistant dosage form for oxidation-sensitive opioids|
|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|
|US20130079749 *||Nov 14, 2012||Mar 28, 2013||Advanced Bionics, Llc||Modular Drug Delivery System for Minimizing Trauma During and After Insertion of a Cochlear Lead|
|USRE28536 *||Mar 4, 1971||Sep 2, 1975||Animal husbandry|
|USRE33994 *||Aug 4, 1989||Jul 14, 1992||Burroughs Wellcome Co.||Pharmaceutical delivery system|
|EP0103387A2 *||Aug 3, 1983||Mar 21, 1984||Pfizer Inc.||Long-acting matrix tablet formulations|
|EP0103387A3 *||Aug 3, 1983||Dec 12, 1984||Pfizer Inc.||Long-acting matrix tablet formulations|
|EP0168522A2 *||Nov 2, 1984||Jan 22, 1986||Akzo Patente GmbH||Active agent-containing shaped article|
|EP0168522A3 *||Nov 2, 1984||Nov 5, 1986||Akzo Patente GmbH||Active agent-containing shaped article|
|EP0345317A1 *||Nov 8, 1988||Dec 13, 1989||Baxter Int||Microcrystalline matrix for administration of beneficial agent.|
|EP0345317A4 *||Nov 8, 1988||Sep 5, 1990||Baxter International Inc. (A Delaware Corporation)||Microcrystalline matrix for administration of beneficial agent|
|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|
|WO1994013267A1 *||Dec 4, 1992||Jun 23, 1994||Rademacher Karl Heinz||Veterinary medicament|
|U.S. Classification||424/469, 424/DIG.700, 514/654, 264/122, 264/118, 514/252.12, D24/101, 264/340, 106/122, 210/483, 424/489, 210/484, 210/348|
|International Classification||A61K9/20, A61K9/26|
|Cooperative Classification||A61K9/2027, Y10S424/07|