GB2215207A - Sustained release pharmaceutical dosage units - Google Patents
Sustained release pharmaceutical dosage units Download PDFInfo
- Publication number
- GB2215207A GB2215207A GB8901833A GB8901833A GB2215207A GB 2215207 A GB2215207 A GB 2215207A GB 8901833 A GB8901833 A GB 8901833A GB 8901833 A GB8901833 A GB 8901833A GB 2215207 A GB2215207 A GB 2215207A
- Authority
- GB
- United Kingdom
- Prior art keywords
- drug
- formulation
- polymer
- formulation according
- tablet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
Abstract
A sustained release pharmaceutical formulation is disclosed having the capability of a linear rate of drug release over a significant period (e.g. at least 20 hours). The formulation essentially comprises a shaped, solid formulation containing a drug and a non-cross-linked hydrophilic polymer which constitutes the binder for the formulation, said polymer having a swell factor between about 50 and 250 % such that when the formulation is contacted with body fluid it swells and becomes soft and rubbery but retains its integrity.
Description
PHARMACEUTICAL FORMULATIONS WITH CONTROLLED DRUG RELEASE
This invention relates to pharmaceutical formulations and in particular to a formulation which is capable of releasing a drug over an extended period of time.
Various methods have been used to achieve sustained release of a pharmacologically active ingredient. For example, in the manufacture of sustained release suppositories, absorbent hydrophilic foams have been immersed in solutions containing the desi.red drug, the foam has then been removed and dried and frequently the procedure repeated to build up a high level of absorbed drug. This is a lengthy and time-consuming process and although the product does give sustained release it does not give a linear rate of drug release, i.e. the release of the drug does not follow zero order kinetics.
British Patent Specificati.on No. 2177708 (Shah) contains a useful review of the prior art and divides controlled drug release systems into two broad types, namely, monolithic (matrix) and reservoir (depot) types.
In the monolithic type, the drug is dispersed or dissolved in a polymer and the rate of release depends on the concentration of the drug in the matrix. Since the concentration falls over time, the rate of release is not constant but follows first order kinetics. The reservoir class involves an encapsulated drug and the drug permeates through the wall of the capsule. Although these systems generally release the drug at a substantially constant rate, there is a danger of failure or damage to the capsule wall which may give rise to rapid release of an overdose level of the drug.
:Various multi-component drug release systems have been proposed in an effort to secure the advantages of both systems but none have proved to be totally satisfactory compromises.
The present invention aims to provide a monolithic type drug release system which is capable of substantially zero order kinetics.
According to one aspect of the present invention there is provided a pharmaceutical formulation which is capable of releasing a drug over an extended period of time, which comprises a shaped, solid formulation containing a drug and a substantially, non-cross-linked hydrophilic polymer which constitutes a binder for the drug, said polymer having a swell factor which is such that on contact with body fluid the formulation swells and becomes soft and rubbery but retains its integrity.
The invention is particularly applicable to the manufacture of tablets or suppositories which can be manufactured by mixing the drug in solid powdered or granular form with the powdered or granular, non-crosslinked hydrophilic polymer and extruding or compression moulding the mixture at elevated temperature to form the desired formulation in the appropriate shape and size.
Other conventional di.luents and fillers normally used in the formulation of tablets and supposi.tori.es can be included in the formulation prior to moulding or extrusion. However, reinforcing fillers are unnecessary since a much stronger shaped formulation is achieved by reason of the formation of a continuous phase of heatflowed polymer in the products of this invention.
By controlling various factors including the concentration of the drug and the geometry of the tablet or suppository and also the nature of the hydrophilic polymer, it is possible to predetermine and control the rate at which the drug is released into the body fluids.
In practice, it has been found that hydrophilic polymers having a water uptake or swell factor between about 60 and 250 percent (preferably 60 to 120 percent) are generally suitable in the practice of the present invention, while preferred drug-loadings in the formulation range from about 5 to 30 percent, preferably 7 to 25 percent. Water uptake or swell factor is defined as:
Weight of hydrated polymer-wei.ght of dry polymer x 100
Weight of dry polymer
The factors mentioned above should be selected so that a tablet is produced which swells and becomes soft and rubbery when taken by mouth or placed in n a body cavity, but retains its integrity and does not break up into particles.In the case of drug-loadings of about 25 percent or more, it is desirable to select polymers having a swell factor at the lower end of the range referred to above, since otherwise the tablets tend to break up when in contact with water or an aqueous fluid. Other factors which have an effect on the rate of drug release are the surface area of the tablet or suppository and the water solubility of the drug.
The hydrophilic non-cross-linked polymers used in the formulations of the present invention are preferably hydrophilic polymers of the kind described in our copending British Patent Application No. 87 11357 (Publication No. 2190387). Such polymers are essentially uncross-linked copolymers of hydrophobi.c monomer components and hydrophilic monomer components, wherein the hydrophobic monomer component is selected from at least one ester of an unsaturated acid of the general formula
CH2 = CRCOOR1, where R is hydrogen or CH3 and R1 is a linear or branched chain alkyl group and wherein the hydrophilic monomer component is selected from one or more of N-vinyl pyrrolidone, acrylic or methacrylic acid and esters of acrylic and methacrylic acid of the general formula CH2 = CRCOOR2, where R is hydrogen or methyl and
R2 is an hydroxy terminated alkyl or alkoxy group.
Preferably, the hydrophilic monomer consists of or comprises N-vinyl pyrrolidone and the hydrophobic monomer is a lower alkyl ester of acrylic or methacrylic acid, e.g. methyl methacrylate.
The hydrophilic nature of the bi.nder depends inter alia on the particular hydrophobic and hydrophilic comonomers and the proportions in which they are copolymerised. An increase in the molar proportions of the hydrophilic component will result in a copolymer having a higher capacity for water absorbtion and accordingly a resultant hydrogel having a higher water content.
The preferred polymers for use in the practice of the present invention are copolymers of methyl methacrylate and N-vinyl pyrrolidone. The polymers are preferably prepared by non-aqueous dispersion polymerisation, for example, as illustrated in Example 9 of our co-pending
British Patent Application No. 87 11357 (Publication No.
2190387).
It is important that the formulation is moulded under pressure so that the particles of hydrophilic monomer cohere and form a tablet or suppository which maintains its integrity when swollen in aqueous fluid. This can be achieved by cold moulding under moulding pressures of the order of 100 meganewtons per square metre, but generally hot moulding is desirable. Preferred moulding temperatures are in the range of 100 to 200 OC (especially 100 to 1600C) and preferred moulding pressures lie within the range of 60 to 120 meganewtons per square metre.
Formulations in accordance with the invention may be prepared more readily than the conventional sustained release formulations. Moreover, the sustained release formulations of the present invention have the additional advantage that a substantially linear rate of drug release can be achieved over a significant period, e.g. at least 6 to 8 hours. Although one may obtain an initial surge of released drug, the rate quickly settles down to a linear relationship until it tails off to a plateau after several hours. This kind of controlled release of drug is what is frequently required and enables drugs to be released at the desired rate throughout the night or when the patient is asleep and is unable to space out the admi.ni.strati.on of his drug therapy.The formulations of the present invention are also particularly useful in treating patients who are incapable of following instructions in taking their medication or, for example, in the controlled administration of analgesic drugs to terminally ill patients.
A further advantage of the present invention is that the formulations can be prepared in standard tablet and suppository moulding machines. It is also possible to manufacture the formulations by hot extrusion of the mixed solid ingredients.
Although tablets and suppositories in accordance with the invention may be manufactured by mixing the ingredients and moulding the shaped formulation in a single operation, more complex structures are possible.
For example, a two or multi.-layer tablet can be manufactured by mixing the same or different hydrophilic polymer with a drug and/or inert filler material and moulding this as a further layer in the tablet so as to achieve a period of no medication or different rate of medication release. A further layer of hydrophilic polymer could also be applied to the tablets or suppositories by a solution coating technique so as to modify the rate of drug release.
It may also be desirable to apply other kinds of coatings to the tablets or suppositories, again to modify the drug release characteristics. For example, an elastic water-impermeable polymeric coating may be applied to the tablet or suppository by solution coating or other techni.que. The coating may be water-permeable or impermeable and in the latter case have one or more holes in it through which the drug would be released. The application of a thin, water-impermeable coating having one or more holes formed therein reduce an initial surge of released drug so that the overall rate of release corresponds even more closely to a zero order rate.
Examples of polymers which may be employed for forming water-impermeable coatings include polymers of vinylidene chloride, polyurethanes and ethylene-vinyl acetate copolymers. Preferred polymers of this type are homopolymers of vinylidene chloride or copolymers thereof with acrylonitrile or vinyl esters.
In the case of water-impermeable coatings a hole should be drilled in the coating, e.g. by using a laser.
Examples of water-permeable coating materials include cellulose derivatives, e.g. cellulose ethers and hydroxy alkyl celluloses.
Another possible way of formulating the compositions of the present invention is to mould the polymer/drug composition into particles having a predetermined size, e.g. about lmm in diameter, and then pressing the particles so formed into a tablet by conventional cold pressing means. In this way, it is possible to form a tablet which would disintegrate rapidly when placed in the stomach into particles of controlled size and this technique is useful to enable one to place the drug in the right place in the body system.
As stated above, the polymers are preferably prepared as powders by non-aqueous dispersion and -polymerisation.
In a series of tests, a range of methyl methacrylate/Nvinyl pyrrolidone copolymers were prepared with MMA/VPd molar ratios of 1:1.2 to 1:0.8.
When the water uptake (or swell factor) of thin films of these polymers was measured t varied from 250% of the dry weight of the polymer to 648. Increasing the vinyl pyrrolidone content increased the water uptake. Polymers with a lower vinyl pyrrolidone content, and hence lower water uptake, are generally preferred for controlled drug release formulations.
A further type of system to which the present invention may be applied is the manufacture of transdermal patches. Some drugs can be administered by direct contact with the skin. An example of this is the treatment of angina where glyceryl trinitrate containing patches are placed on the patients chest. Such a system may be formulated in accordance with the present invention by forming a sheet of polymer (swollen with a suitable swelling agent, such as propanol) having the drug distributed therein. The sheet may be formed by mixing the drug and the hydrophilic polymer and calendaring the mixture under heat and pressure and subsequently hydrating it to form a hydrogel. Alternatively, the sheet may be extruded or cast from solution.
While reference has been made in the foregoing description to systems for the sustained release of drugs, it will be appreciated that the invention may also be applied to the sustained release of diagnostic agents.
Example 1
The same polymerisation process was used to prepare all the copolymers, only the weights of reactants used were varied. In this Example, a 1:0.8 MMA:VPd copolymer was prepared by placing a mixture of methyl methacrylate (8.0g), vinyl pyrrolidone (20.0g), a graft dispersant precursor (11.2g) based on polylauryl methacrylate (prepared by the method described on page 107 of "Di.spersion Polymerisation in Organic Media", edited by
K.E.J. Barrett and published by Wiley), dilauryl peroxide (0.4g) and petroleum spirit boiling range 60-800C (960g) in a flask fitted with a mechanical stirrer, a nitrogen inlet, a non-reflux condenser and the means for returning cold, condensed distillate to the flask.After flushing the apparatus and the mixture with oxygen-free nitrogen, the stirred mixture was heated by means of a water bath so that about 3 ml/minute of distillate was condensed and returned to the flask. An oxygen-free atmosphere was maintained throughout the apparatus at all times. After the mixture had boiled for one hour a mixture of methyl methacrylate (8.0g), vinyl pyrrolidone (20.0g), graft dispersant precursor (3.2 g) and azo-.di isobutyronitrile (0.08g) was added at the rate of 1.2 ml every three minutes into the stream of cold distillate returning to the flask.When the addition of this mixture was complete a further mixture of methyl methacrylate (50.0g), vinyl pyrrolidone (54.0 g) and dilauryl peroxide (0.32g) was added in the same way, and then a mixture of methyl methacrylate (40.0 g) and dilauryl peroxide (0.08 g).
The rate of addition was increased to 2.8 ml every 3 minutes, three hours after the making of additions was begun. After completion of all the additions, the mixture was boiled gently for four hours, with the distillate being returned to the flask, and then allowed to cool under nitrogen before stirring was discontinued.
A white dispersion of particles of copolymer in petroleum spirit was obtained, which on evaporation of the petroleum spirit gave a free-flowing fine power which, on testing in a thin film, had a swell factor of 648.
Example 2
Example 1 was repeated except that the proportions of the reactants were as follows:
Initial 1st 2nd Total
Mixture Addition Addition
Mixture Mixture
Methyl methacrylate 2.0g 4.0 49.9 55.8
Vinyl pyrrolidone 24.8 24.0 35.2 84.0
Graft dispersant precursor 16.0 8.0 24.0 Dilauroyl peroxide 0.36 0.8 0.36 1.52 60-80 Pet.spirit 900 900
The resulting copolymer when tested in a thin film as described in Example 1 has a swell factor of 195%.
TECHNIQUE FOR MOULDING TABLETS
Pellets of the hydrophilic polymer obtained above and the sodium salt of salicylic acid, to represent a watersoluble drug, were compression moulded by the following technique:
The required quantities of dry powdered polymer and the sodium salt of salicylic acid (obtained from the
Aldrich Chemical Co. Ltd.) were ball-milled together for 12 hours, to reduce the particle size of the latter and to produce an intimate mixture of the two materials. 0.4 g of the mixture were placed in a stainless steel mould having a circular cavity of 1.3 cm diameter, and the mould heated between the platens of a hydraulic press, which had been preheated to 1800C.After 20 minutes, a force of 1300N, giving a pressure on the tablet of 100MN/m2, was applied to the mould for 20 minutes, and the mould then removed from the press and allowed to cool under a light pressure in a screw press. A hard, circular pellet 0.4 cm thick was obtained by this means. A variety of polymers having different MMA:VPd molar ratios were also used, and also drug loadings of 10% and 25% were employed.
Higher moulding pressures were found to be unnecessary.
DETERMINATION OF DRUG RELEASE RATE
A moulded drug-containing tablet prepared as described above, was suspended in a net in deionised water (200 ml) in a glass vessel. The drug (sodium salicylate) constituted 10% by weight of the tablet and the polymer was a 1:0.8 molar MMA:VPd copolymer. The water was stirred at a constant rate with a magnetic stirrer and maintained at 18-200C. At convenient intervals over a one week period a sample of water was taken for analysis and the rest of the water replaced with fresh deionised water.
The sodium content of the sample of water was determined by atomic adsorption spectroscopy and the amount of drug released calculated. A graph of the cummulative release of sodium salicylate against time was plotted and is shown in Figure 1. As shown in Figure 1, approximately 65% of the drug was released at a constant rate over a one day period, followed by virtually no further release.
PREPARATION OF COATED TABLETS
The polymer obtained in Example 1 was mixed with sodium salicylate to provide a mixture containing 25% by weight of the drug. A tablet was formed from the mixture by compression moulding as described above using a moulding pressure of 100 MN/m2 and a mould temperature of 1300C. After moulding, the tablet was coated with a layer of polyvinylidene chloride copolymer (Saran F.310) by dissolving the Saran F.310 in methyl ethyl ketone to form a 25% solution and dipping the tablet in the solution. A dried coating between 20 to 50 um thick was obtained. A hole was drilled in the tablet using a 1/4 mm drill. Using the technique described above, the rate of drug release was determined and the results plotted graphically in Figure 2.
Claims (15)
1. A pharmaceutical formulation which is capable of releasing a drug over an extended period of time, which comprises a shaped, solid formulation containing a drug and a substantially, non-cross-linked hydrophilic polymer which constitutes a binder for the drug, said polymer having a swell factor which is such that on contact with body fluid the formulation swells and becomes soft and rubbery but retains its integrity.
2. A formulation according to claim 1 in which the hydrophilic polymer has a swell factor of between 50 and 250 per cent.
3. A formulation according to claim 1 or claim 2 in which said formulation is a tablet or suppository which has been formed by compression moulding.
4. A formulation according to claim 3 in which said tablet or suppository has been moulded at a temperature of from 100 to 1600C.
5. A formulation according to claim 3 in which said suppository has been formed by extrusion at a temperature of at least 1000C.
6. A formulation according to any one of the preceding claims in which the hydrophilic polymer has a swell factor between 60 and 120 per cent.
7. A pharmaceutical formulation which is capable of sustained release of a drug at a zero order rate, which comprises a shaped, solid formulation containing a drug and a binder comprising a substantially non-cross-linked hydrophilic polymer, said polymer having a swell factor between 50 and 250 per cent.
8. A formulation according to any one of the preceding claims in which the drug is water-soluble.
9. A formulation according to claim 8 in which the drug is present in an amount of from 5 to 30 per cent by weight of the total formulation.
10. A formulation according to any one of the preceding claims which is enveloped in a coating of a second polymer which has a low permeability to water.
11. A formulation according to claim 10 in which the second polymer is a polymer or copolymer of vinylidene chloride.
12. A formulation according to claim 10 or 11 in which the coating has a small hole.
13. A formulation according to any one of the preceding claims in which the hydrophilic polymer is a polymer of a hydrophilic monomer selected from one or more of N-vinyl pyrrolidone and hydroxy alkyl esters of methacrylic or acrylic acid and a hydrophobic monomer selected from a lower alkyl ester of acrylic or methacrylic acid.
14. A process for preparing a pharmaceutical formulation which comprises mixing a water-soluble drug with a solid, particulate non-cross-linked hydrophi.li.c polymer and extruding or compressing the resulting mixture at elevated temperature to form a tablet or suppository.
15. A process according to claim 14 which is carried out at a temperature of from 100 to 1600C.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB888801863A GB8801863D0 (en) | 1988-01-28 | 1988-01-28 | Pharmaceutical formulations with controlled drug release |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB8901833D0 GB8901833D0 (en) | 1989-03-15 |
| GB2215207A true GB2215207A (en) | 1989-09-20 |
Family
ID=10630652
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB888801863A Pending GB8801863D0 (en) | 1988-01-28 | 1988-01-28 | Pharmaceutical formulations with controlled drug release |
| GB8901833A Withdrawn GB2215207A (en) | 1988-01-28 | 1989-01-27 | Sustained release pharmaceutical dosage units |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB888801863A Pending GB8801863D0 (en) | 1988-01-28 | 1988-01-28 | Pharmaceutical formulations with controlled drug release |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU3041789A (en) |
| GB (2) | GB8801863D0 (en) |
| WO (1) | WO1989006957A1 (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0951278A2 (en) * | 1997-01-03 | 1999-10-27 | ELAN CORPORATION, Plc | Sustained release cisapride mini-tablet formulation |
| DE19814730A1 (en) | 1998-04-02 | 1999-10-07 | Basf Ag | Pharmaceutical and cosmetic compositions with matrix containing N-vinyllactam or N-vinylamine based copolymer |
| DE19843904A1 (en) | 1998-09-24 | 2000-03-30 | Basf Ag | Solid dosage form for prolonged slow release of e.g. drugs, plant treatment agents, or food or feed additives, containing copolymer of N-vinyl-lactam, methyl methacrylate and further monomer(s) as binder |
| DE19843903A1 (en) * | 1998-09-24 | 2000-03-30 | Basf Ag | Solid dosage form for prolonged slow release of e.g. drugs, plant treatment agents or food or feed additives, containing copolymer of N-vinyl-lactam and methyl methacrylate as binder |
| US8309112B2 (en) * | 2003-12-24 | 2012-11-13 | Advanced Cardiovascular Systems, Inc. | Coatings for implantable medical devices comprising hydrophilic substances and methods for fabricating the same |
| US9011831B2 (en) | 2004-09-30 | 2015-04-21 | Advanced Cardiovascular Systems, Inc. | Methacrylate copolymers for medical devices |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1085739A (en) * | 1962-09-12 | 1967-10-04 | Parke Davis & Co | Controlled release medicaments (and process for producing the same) |
| GB2090535A (en) * | 1981-01-06 | 1982-07-14 | Osman Mohammad Fekry | Medical inserts |
| EP0092918A2 (en) * | 1982-04-22 | 1983-11-02 | Imperial Chemical Industries Plc | Continuous release formulations |
| GB2143733A (en) * | 1983-07-22 | 1985-02-20 | Nat Res Dev | Controlled release device comprising a hydrogel |
| GB2144051A (en) * | 1983-03-02 | 1985-02-27 | Neil Bonnette Graham | Hydrogel-containing envelopes |
| GB2145422A (en) * | 1983-08-26 | 1985-03-27 | Sandoz Ltd | Novel poly-esters, their preparation and pharmacological use thereof |
| GB2150938A (en) * | 1983-12-05 | 1985-07-10 | Tyndale Plains Hunter Limited | Hydrophilic polyurethane acrylate compositions |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1125698A (en) * | 1978-03-09 | 1982-06-15 | Masaru Yoshida | Process for preparing a polymer composition |
| US4624848A (en) * | 1984-05-10 | 1986-11-25 | Ciba-Geigy Corporation | Active agent containing hydrogel devices wherein the active agent concentration profile contains a sigmoidal concentration gradient for improved constant release, their manufacture and use |
-
1988
- 1988-01-28 GB GB888801863A patent/GB8801863D0/en active Pending
-
1989
- 1989-01-27 AU AU30417/89A patent/AU3041789A/en not_active Abandoned
- 1989-01-27 GB GB8901833A patent/GB2215207A/en not_active Withdrawn
- 1989-01-27 WO PCT/GB1989/000076 patent/WO1989006957A1/en unknown
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1085739A (en) * | 1962-09-12 | 1967-10-04 | Parke Davis & Co | Controlled release medicaments (and process for producing the same) |
| GB2090535A (en) * | 1981-01-06 | 1982-07-14 | Osman Mohammad Fekry | Medical inserts |
| EP0092918A2 (en) * | 1982-04-22 | 1983-11-02 | Imperial Chemical Industries Plc | Continuous release formulations |
| GB2144051A (en) * | 1983-03-02 | 1985-02-27 | Neil Bonnette Graham | Hydrogel-containing envelopes |
| GB2143733A (en) * | 1983-07-22 | 1985-02-20 | Nat Res Dev | Controlled release device comprising a hydrogel |
| GB2145422A (en) * | 1983-08-26 | 1985-03-27 | Sandoz Ltd | Novel poly-esters, their preparation and pharmacological use thereof |
| GB2150938A (en) * | 1983-12-05 | 1985-07-10 | Tyndale Plains Hunter Limited | Hydrophilic polyurethane acrylate compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8801863D0 (en) | 1988-02-24 |
| AU3041789A (en) | 1989-08-25 |
| WO1989006957A1 (en) | 1989-08-10 |
| GB8901833D0 (en) | 1989-03-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |