CA1332809C - Sustained release pharmaceutical compositions - Google Patents
Sustained release pharmaceutical compositionsInfo
- Publication number
- CA1332809C CA1332809C CA000548872A CA548872A CA1332809C CA 1332809 C CA1332809 C CA 1332809C CA 000548872 A CA000548872 A CA 000548872A CA 548872 A CA548872 A CA 548872A CA 1332809 C CA1332809 C CA 1332809C
- Authority
- CA
- Canada
- Prior art keywords
- composition according
- hydroxypropyl methylcellulose
- acetylsalicylic acid
- microcrystalline cellulose
- weight ratio
- 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.)
- Expired - Lifetime
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Abstract
A sustained release pharmaceutical composition comprising a pharmacologically active agent in admixture with a) microcrystalline cellulose and b) hydroxypropyl methyl-cellulose wherein the weight ratio of a) to b) is at least 1 to 1 is described. Aspirin is the preferred active agent.
Description
-1- 1 3~80~
SUSTAINED RELEASE PEIAR~l~CEUTICAL CO~POS ITIONS
This invention relates to sustained release pharmaceutical compositions.
We have surprisingly found that a solid oral sustained release formulation may be produced from the readily available and widely approved exci~ients microcrystalline cellulose and hydroxypropyl methylcellulose.
The invention accordingly provides in one aspect a sustained release pharmaceutical composition comprising a pharmacolo-gically active agent in admixture with a) microcrystallinecellulose and b) hydroxypropyl methylcellulose wherein the weight ratio of a) to b) is at least 1 to 1, with the proviso that when the active agent is other than acetylsali-cylic acid in free form or salt form, the active agent is also in admixture with pregelatinized starch.
In an other aspect the invention provides a process for the production of a sustained release pharmaceutical composition which comprises mixing a pharmacologically active agent and a) microcrystalline cellulose and b) hydroxypropyl methyl-cellulose wherein the weight ratio of a) to b) is at least1 to 1, with the proviso that when the active agent is other than acetylsalicylic acid in free form or salt form, the active agent is also in admixture with pregelatinized starch.
A wide variety of pharmacologically active agents (herein-after "agents") may be used. These may include water-soluble or water-insoluble compounds. The agents may be moisture sensitive or not. The dosage of agent may vary between wide limits.
-la- 1 3 ~ ?~119 representative active agents include analgesics, anti-pyretics, anti-inflammatories, anti-histamines, anti-hyper-tensives, vasodilators, transquillizers, anti-depressants, neuroleptics, vasoconstrictors, anti-convulsants, anti-asth~atics, etc.
1 3 '`2809 The invention is exemplified hereinafter by reference to acetylsalicylic acid (hereinafter ASA) but it is to be understood that it is applicable to any active agent.
The ASA is preferably in the form of the free acidO
Alternatively it may be in the form of a salt, e.g. a sodium or calcium saltO The ASA is preferably in the form of fine crystals e.g. of particle size under 40 mesh, e.g.
5 to 40 meshO
Preferably the mean polymerisation number of the microcry-stalline cellulose is from about 200 to 2000, preferably 200 to 300O Preferred mean molecular weights are from about 20,000 to about 100,000 e.gO 30,000 to 50,000. Preferably the mean particle size is from about 5 to about 140 microns.
Preferably the particle sizeufrom 20 to 100 microns, e.g.
to 80 micronsO Conveniently the specific gravity is about 1040 to 10600 Conveniently the microcrystalline cellulose is obtained by mechanical treatment of glucose-based poly-saccharides, eOgO native cellulose, optionally with acidic treatment.
Preferred forms are the AVICEL brand (Registered Trade Mark of FMC Corporation).
Conveniently the methoxy content of the hydroxypropyl methyl-cellulose i 5 from about 15 to about 34 per cent by weight, preferably from about 19 to 30, especially 19 to 24, per cent by weight. Preferably the hydroxypropyl content is from about 4 to about 32 per cent by weight, preferably from 4 to 12 per cent by weightO
~ 3 ~80'~
The viscosity of the hydroxypropyl methylcellulose is conveniently from about 15 to about 50,000 cps (based on a 2 percent by weight aqueous solution at 20 degrees centigrade) e.g. 4000 to 50,000 cps.
Conveniently the mean molecular weight is from about 20,000 to 200,000, e.g. 90,000 to 130,000.
Preferred forms of hydroxypropyl methylcellulose are those available under the trade marks of Methocel A, K and E from the Dow Chemical Company Michigan.
Preferably the weight ratio of microcrystalline cellulose to hydroxypropyl methylcellulose is from about 10:1 to 1:1, e.g.
SUSTAINED RELEASE PEIAR~l~CEUTICAL CO~POS ITIONS
This invention relates to sustained release pharmaceutical compositions.
We have surprisingly found that a solid oral sustained release formulation may be produced from the readily available and widely approved exci~ients microcrystalline cellulose and hydroxypropyl methylcellulose.
The invention accordingly provides in one aspect a sustained release pharmaceutical composition comprising a pharmacolo-gically active agent in admixture with a) microcrystallinecellulose and b) hydroxypropyl methylcellulose wherein the weight ratio of a) to b) is at least 1 to 1, with the proviso that when the active agent is other than acetylsali-cylic acid in free form or salt form, the active agent is also in admixture with pregelatinized starch.
In an other aspect the invention provides a process for the production of a sustained release pharmaceutical composition which comprises mixing a pharmacologically active agent and a) microcrystalline cellulose and b) hydroxypropyl methyl-cellulose wherein the weight ratio of a) to b) is at least1 to 1, with the proviso that when the active agent is other than acetylsalicylic acid in free form or salt form, the active agent is also in admixture with pregelatinized starch.
A wide variety of pharmacologically active agents (herein-after "agents") may be used. These may include water-soluble or water-insoluble compounds. The agents may be moisture sensitive or not. The dosage of agent may vary between wide limits.
-la- 1 3 ~ ?~119 representative active agents include analgesics, anti-pyretics, anti-inflammatories, anti-histamines, anti-hyper-tensives, vasodilators, transquillizers, anti-depressants, neuroleptics, vasoconstrictors, anti-convulsants, anti-asth~atics, etc.
1 3 '`2809 The invention is exemplified hereinafter by reference to acetylsalicylic acid (hereinafter ASA) but it is to be understood that it is applicable to any active agent.
The ASA is preferably in the form of the free acidO
Alternatively it may be in the form of a salt, e.g. a sodium or calcium saltO The ASA is preferably in the form of fine crystals e.g. of particle size under 40 mesh, e.g.
5 to 40 meshO
Preferably the mean polymerisation number of the microcry-stalline cellulose is from about 200 to 2000, preferably 200 to 300O Preferred mean molecular weights are from about 20,000 to about 100,000 e.gO 30,000 to 50,000. Preferably the mean particle size is from about 5 to about 140 microns.
Preferably the particle sizeufrom 20 to 100 microns, e.g.
to 80 micronsO Conveniently the specific gravity is about 1040 to 10600 Conveniently the microcrystalline cellulose is obtained by mechanical treatment of glucose-based poly-saccharides, eOgO native cellulose, optionally with acidic treatment.
Preferred forms are the AVICEL brand (Registered Trade Mark of FMC Corporation).
Conveniently the methoxy content of the hydroxypropyl methyl-cellulose i 5 from about 15 to about 34 per cent by weight, preferably from about 19 to 30, especially 19 to 24, per cent by weight. Preferably the hydroxypropyl content is from about 4 to about 32 per cent by weight, preferably from 4 to 12 per cent by weightO
~ 3 ~80'~
The viscosity of the hydroxypropyl methylcellulose is conveniently from about 15 to about 50,000 cps (based on a 2 percent by weight aqueous solution at 20 degrees centigrade) e.g. 4000 to 50,000 cps.
Conveniently the mean molecular weight is from about 20,000 to 200,000, e.g. 90,000 to 130,000.
Preferred forms of hydroxypropyl methylcellulose are those available under the trade marks of Methocel A, K and E from the Dow Chemical Company Michigan.
Preferably the weight ratio of microcrystalline cellulose to hydroxypropyl methylcellulose is from about 10:1 to 1:1, e.g.
3:1 to 1:1, e.g. 3:1 to 2:1.
Preferably the weight ratio of microcrystalline cellulose to agent is from 1:5 to 1:10, e.g. 1:6 to 1:7.5, especially 1:6.5 to 1:7. Conveniently pregelatinized starch is present.
Conveniently the starch is soluble to an extent of about 5 to 25, e.g. 10 to 20, percent by weight in cold water. Suitably the pregelatinized starch is made by reacting starch, preferably corn starch (based on 80 percent amylopectin moieties and 20 percent amylose moieties) so as to break down hydrogen bonding between the amylose and amylopectin moieties therein. Conveniently the product contains from 60 to 85 percent by weight of corn starch, the remainder being free amylose and amylopectin.
Preferably the weight ratio of pregelatinized starch to hydroxypropyl methylcellulose is from about 1:1 to about 1:5, e.g. to about 1:2.
;' Naturally other excipients may be present. These excipients may be those conventionally used in pharmaceutical formula-tions, such as anti-frictional agents, e.g. lubricants such as stearic acid or magnesium stearate, and 91idants such as silicon dioxide, anti-adherents/soluble fillers such as lactose, flavouring agents and colourants.
Conveniently the weight ratio of agent to all other excipients present is from about 0O2 1 to about 0.4: 1, e.g. from about 2: 1 to 4: 1. Conveniently the hydroxypropyl methylcellulose content is from about 5 to 10 per cent of the total weight, e.g.
6 to 9 per cent, especially 6.5 or 8.5 per cent.
The pharmaceutical composition is preferably in solid form.
Prefera61y it is in~a unit dose form. Conveniently it is in the form of a tablet.
Conveniently the amount of ASA per unit dose is from 300 to 400 mg or 600 to 700 mg.Such pharmaceutical compositions may be produced by techniques well known in the art.
Tablets are preferably compressed to a hardness of from about 8 to 12 kiloponds (based on the Heberlein method).
The bioavailability of the compositions of the invention may be determined in conventional manner.
In a typical trial ASA pharmaceutical compositions of the invention are administered at 7 am, 3 pm, 11 pm or 7 am and 7 pm.
Immediate release ASA compositions are administered at 7 am, 11 am, 3 pm, 7 pm and 11 pm, as reference formulations.
Free and total salicylic acid (SA) may be measured in conven-tional manner by HPLC (essentially that of Hamson et al, J.Pharm.Sci`. (1980) 69 1268).
1 3~2809 -5- 100-6~70 Free SA detection method Heparinized blood samples are collected. Plasma is sepa-rated within 15 minutes of drawing blood, divided into 2 por-tions and placed in polypropylene tubes sealed with colour-coded polypropylene plugs.
0.5 ml Samples are acidified with 1 drop of concentrated phosphoric acid for a few minutes, and extracted with toluene/
ethyl acetate (50:50). TH~ extracts are analysed using re-verse phase HPLC with UV detection at 305 mm using 3,4-dimethoxy-beinzoic acid as internal standard. The method gives a minimum quantifiable level of 0.1 microgram per milli-litre of free SA.
Total SA detection method Total SA is determined from urine as salicylic acid. Each 1 ml urine sample was mixed with 1 ml of concentrated hydro-chloric acid, sealed and heated for 16 hours at 98C. The sample is allowed to cool. 1 ml acetonitrile is added con-taining the internal standard. The samples are subjected to HPLC analysis and the SA detected by ultra-violet spectroscopy at 313 mm.
The bioavailability trials are preferably continued for at leas-t eight days. Further details are apparent from the trials described hereinafter. The measured mean salicylate concen-trations show an unexpectedly high availability of free salicylate in the blood from the pharmaceutical compositions of the invention, especially at anti-inflammatory therapeutic levels.
Preferably the weight ratio of microcrystalline cellulose to agent is from 1:5 to 1:10, e.g. 1:6 to 1:7.5, especially 1:6.5 to 1:7. Conveniently pregelatinized starch is present.
Conveniently the starch is soluble to an extent of about 5 to 25, e.g. 10 to 20, percent by weight in cold water. Suitably the pregelatinized starch is made by reacting starch, preferably corn starch (based on 80 percent amylopectin moieties and 20 percent amylose moieties) so as to break down hydrogen bonding between the amylose and amylopectin moieties therein. Conveniently the product contains from 60 to 85 percent by weight of corn starch, the remainder being free amylose and amylopectin.
Preferably the weight ratio of pregelatinized starch to hydroxypropyl methylcellulose is from about 1:1 to about 1:5, e.g. to about 1:2.
;' Naturally other excipients may be present. These excipients may be those conventionally used in pharmaceutical formula-tions, such as anti-frictional agents, e.g. lubricants such as stearic acid or magnesium stearate, and 91idants such as silicon dioxide, anti-adherents/soluble fillers such as lactose, flavouring agents and colourants.
Conveniently the weight ratio of agent to all other excipients present is from about 0O2 1 to about 0.4: 1, e.g. from about 2: 1 to 4: 1. Conveniently the hydroxypropyl methylcellulose content is from about 5 to 10 per cent of the total weight, e.g.
6 to 9 per cent, especially 6.5 or 8.5 per cent.
The pharmaceutical composition is preferably in solid form.
Prefera61y it is in~a unit dose form. Conveniently it is in the form of a tablet.
Conveniently the amount of ASA per unit dose is from 300 to 400 mg or 600 to 700 mg.Such pharmaceutical compositions may be produced by techniques well known in the art.
Tablets are preferably compressed to a hardness of from about 8 to 12 kiloponds (based on the Heberlein method).
The bioavailability of the compositions of the invention may be determined in conventional manner.
In a typical trial ASA pharmaceutical compositions of the invention are administered at 7 am, 3 pm, 11 pm or 7 am and 7 pm.
Immediate release ASA compositions are administered at 7 am, 11 am, 3 pm, 7 pm and 11 pm, as reference formulations.
Free and total salicylic acid (SA) may be measured in conven-tional manner by HPLC (essentially that of Hamson et al, J.Pharm.Sci`. (1980) 69 1268).
1 3~2809 -5- 100-6~70 Free SA detection method Heparinized blood samples are collected. Plasma is sepa-rated within 15 minutes of drawing blood, divided into 2 por-tions and placed in polypropylene tubes sealed with colour-coded polypropylene plugs.
0.5 ml Samples are acidified with 1 drop of concentrated phosphoric acid for a few minutes, and extracted with toluene/
ethyl acetate (50:50). TH~ extracts are analysed using re-verse phase HPLC with UV detection at 305 mm using 3,4-dimethoxy-beinzoic acid as internal standard. The method gives a minimum quantifiable level of 0.1 microgram per milli-litre of free SA.
Total SA detection method Total SA is determined from urine as salicylic acid. Each 1 ml urine sample was mixed with 1 ml of concentrated hydro-chloric acid, sealed and heated for 16 hours at 98C. The sample is allowed to cool. 1 ml acetonitrile is added con-taining the internal standard. The samples are subjected to HPLC analysis and the SA detected by ultra-violet spectroscopy at 313 mm.
The bioavailability trials are preferably continued for at leas-t eight days. Further details are apparent from the trials described hereinafter. The measured mean salicylate concen-trations show an unexpectedly high availability of free salicylate in the blood from the pharmaceutical compositions of the invention, especially at anti-inflammatory therapeutic levels.
The trials as described hereinafter show the non-linearity of ASA kinetics since the 0-8 hour AUC for free salicylate for a dose of 3.9 gram ASA (1300 mg ASA given 3 times a day in Trial A) at a dose of 3.9 9 ASA is disproportionately higher than that for 2O6 gram ASA ( 1300 mg given twice a day in Trial B). The urine excretion data show that for doses of 206 9 ASA and 3O9 9 ASA the cumulation excretion of total SA is similar and independent of dose.
These results suggest that at high doses of ASA at which an anti-inflammatory effect occurs there is a constant satu-ration of metabolic pathways (as indicated by the dose-in-dependent cumulative urinary excretion values). We have found that the plasma concentration of free SA increases dispro-portionately to the dose at high doses of ASA. We believe that this may be due to a combination of the effect of clearance of the unbound ASA and the ratio of protein-bound SA to unbound SA in plasma. When metabolism is saturable clearance should decrease but when protein binding is saturated clearance increases. Therefore the steady state concentration of free SA may depend on the magnitude of each of these two effects.
The pharmaceutical compositions of the invention have a longer elimination half life (e.g. greater than 9 hours) than that of immediate release ASA pharmaceutical compositions. In the case of immediate release ASA compositions large peak-to-trough ratios of free SA may occur which may provide periods of in-creased metabolism of SA resulting in lower steady state levels.
The pharmaceutical compositions of the invention on the other hand provide therapeutic concentrations of SA at lower daily doses than immediate release ASA pharmaceutical compositions.
and have less GI-irritating potential.
1 3 280q The pharmaceutical compositions of the invention may be administered for all indications that ASA is indicated for~
in particular pains of rheumatism, arthritis, lumbago, neuralgia, neuritis, sciatica and bursitis (anti-inflammatory indications)~ fever and cerebral ischemic attacks.
~or anti-inflammatory indications a dose of about 600 to 1300, e.g. 650 to 1300 mg, ASA every 8 to 12 hours is satis-factory~ Daily doses contemplated are from about 2.6 to about 3.9 9. Analgesic and anti-pyretic indicated doses are from about 300 to about 700 mg, e.g. 325 to 650 mg. For rheumatic fever daily doses of 100 mg ASA/kg body weight may be given in divided doses every 8 to 12 hours to counter-act pain, swelling and fever. For cerebral ischemic attacks an indicated dose is 650 mg every 12 hours.
In another aspect the present invention provides an oral solid pharmaceutical composition comprising at least 300 mg acetyl-salicylic acid in sustained release form and capable of providing in the steady state on administration of an acetylsalicylic acid daily dose of 2.6 9 in divided doses 2 or 3 times a day a si~nifi-cantly higher blood plasma free salicylic acid concentration than that obtained on administration of immediate release acetylsali-cylic acid tablets given at the same daily dose in divided doses every 4 hours.
Conveniently the pharmaceutical composition contains 300 to 700 mg ASA and has dissolution rate at 37 C in water of from 15 to 40 per cent in 1 hour and not less than 70 9O/ at 8 hours.
Prefera~ly in 1 hour from 20 to 35 per cent is released.
Conveniently at 8 hours from 70 to 90 per cent eOg. 80 to 90 per cent is releasedO
- 1 3S280~ 100-6970 The following examples illustrate the invention.
In the Examples:
Microcrystalline cellulose has a molecular weight of from 30,000 to 50,000: ~mean particle size 30-100 microns; specific gravity 1055; tap volume 0.30 to 0.80~ The material used was the brand Avicel PH 102 (Registered Trade Mark) available from FMC Corporation, Marcus Hook, USA. It complies with specifications given for microcrystalline cellulose in USP/National Formulary XXI.
Hydroxypropyl methylcellulose 2208 has a number average molecular weight of 120,000; viscosity approx. 15,000 cps:
a 19-24 per cent hy weight methoxyl content and a 4-12 per cent by weight hydroxypropyl content. Used was brand Methocel K15M Premuim (Registered Trade Mark) available from Dow Chemical Company Michigan USA. It complies with specifications given for hydroxypropyl methylcellulose 2208 in USP XXI.
Pregelatinized Starch is a modified corn starch and comprises 5 per cent amylose, 15 per cent amylopectin and 80 per cent unmodified corn starch. It is partially cold water soluble.
The material used was the brand Starch 1500 (Registered Trade Mark) available from Colorcon Inc., West Point, Pennsylvania.
USA. It complies with the specifications given for pregela-tinized starch in USP / National Formulary XXI.
Colloidal silicon dioxide was the brand Cab-0-Sil (Registered Trade Mark) available from Cabot Corporation, Boston, Mass.USA.
It complies with the specifications given in USP/~National Formulary XXI.
The ASA used are 40 mesh crystals. The immediate release for-mulation used as reference in the bioavailability trials was brand Bayer Aspirin (Registered Trade Mark).
3 .S 2 ~ O q Further specifications for the above products are available in Manufacturer's brochures and in Lexikon der Hilfsstoffe by H.P.Fiedler. Second Edition 1981~ Editio Cantor~Aulen-dorf, WOGermanyO
All other ingredients used meet the specifications laid down by the USP XXIo 1 3s280~
EXAMPLE 1: 325 m~ ASA tablets __.___ ____ _ _____ mg/tahlet ASA 325.000 Microcrystalline cellulose 47.500 Hydroxypropyl methylcellulose 27.625 Pregelatinized Starch 22.100 Stearic Acid 2.125 Colloidal Silicon Dioxide 0.650 A charge to make up 1 million tablets is made up as follows:-The above quantities are multipled by 1 million,e.g. 325 kgacetylsalicylic acid are used. 50 kg of acetylsalicylic acid are mixed with the silicon dioxide. The remaining acetylsali-cylic acid, hydroxypropyl methylcellulose, silicon dioxide/
acetylsalicylic acid mixture, microcrystalline cellulose and pregelatinized starch are introduced in an alternating fashion into a 30 cubic feet twin shell blender. Mixing is effected for 15 minutes. 40 kg of the mixture is removed. The remaining mixture is passed through a 20 mesh (aperture size 1.00 mm ;
wire diameter 0.63 mm) stainless steel screen on an oscilla-ting granulator~ The 40 kg unscreened mixture and the stearic acid are mixed for 5 minutes, screened through a 20 mesh stain-less steel screen as described above with an oscillating granu-lator, and mixed ~ith the previously screened mixture. Mixing is effected.for 15 minutes using a tumbling action to produce a granulate. The granulate is then tabletted on a rotary tablet press. Tablet weight 425 mg. Thickness 4.68 - 4.85 mm. Hardness 8-12 Kiloponds (Heberlein method).
Dissolution release data (average of 6 tablets) in water at 37C:
Per cent release of ASA
Lot 1 Lot 2 1 hour 23.1 30.3 2 hour 39.4 45.4 3 hour 51.2 57.0 4 hour 61.4 65.9 6 hour 72.5 76.5 8 hour 80.7 &6.6 12 hour 87.1 93.6 EXAMPLE 2: 650 m~ ASA tablets In analogous manner to that disclosed in Example 1 are pro-duced tahlets each containing:
mg/tablet ASA 650.000 Microcrystalline cellulose 95.000 Hydroxypropyl methylcellulose55.25 Pregelatinized Starch 44.20 Stearic Acid 4.25 Colloidal Silicon Dioxide 1.30 The batch size is for 500,000 tablets. The resultant tablets have a weight each of 850 mg and thi-ckness 6.25 to 6.40 mm.
~issolution release date (average of 6 tablets) in water at 37~C:-Per cent release of ASA
Lot 1 Lot 2 1 hour 21.5 26.8 2 hour 34.4 39.9 3 hour 44.2 49.8 4 hour 53-4 57-7 6 hour 66.1 69.0 8 hour 75.7 77.1 12 hour 86.9 85.7 -12- 10~-6970 1 ~32809 Trial A:
Steady State Bioavailability of 1300 mg ASA according to the i~nvention administered 3 times a day The pharmaceutical composition of the invention described in example 2 (650 mg ASA tablet) was administered at a dose of 2 tablets to 12 healthy male volunteers at 7 am, 3 pm and 11 pm on days 1 to 8 and at 7 am on day 9. The total daily dose was 3.9 9 ASA.
An immediate release formulation was given at a dose of 325 mg tablets every 4 hours from 7 am to 11 pm on days 1 to 8 and at 7 am and 11 am on day 9. The total daily dose was 3~25 9 ASA.
Each subject received the two formulations in a 9 day study session according to a random sequence. The wash-out period at the end of the study session was 6 days.
Blood samples were obtained on day 8 at 7 am (pre-dose) and 11 am (pre-dose) and on day 9 at 7 am (pre-dose) and 1, 2, 3, 4 (pre-dose in the case of the immediate release formu-lation), 5, 6, 8, 10 and 12 hours following drug administra-tion at 7 am.
Statistical evaluation for both formulation on days 8 and 9 indicated that both were at the steady state for the day 9 bioavailability study.
The results obtained for the measurement of free plasma salicylate in the blood were as follows (REFERENCE = imme-diate release formulation):-_13_ 100-6970 1 3 ~2809 Results:
Day 9 (Steady-State) Mean Plasma Salicylate Concentrations (mcglmL) 3.9 G/day 3.25 G/day Sampling Time EXAMPLE 2 REFERENCE
(hour) 2 x 650 mg q8h 2 x 325 mg q4h 0 113.90 + 56.14* 56.29 + 36.90 1.00 117.91 + 56.02* 68.55 + 37.07 2.00 114.17 + 57.27* 72.53 + 31.12 3.00 118.58 + 61.07* 68.54 + 39.81 4O00 117015 + 59.25* 54.49 + 32.29 5.00 115.66 + 58.85* 67.02 + 27.50 6000 111082 + 57.34* 64.28 + 21.55 8.00 94.20 + 57.19* 54.57 + 29.53 10.00 82.82 + 49.36* 41.94 + 26.46 12000 68.11 + 52007* 30.02 + 23.23 * The two formulations differ statistically at the 5 level or greater.
Pharmacokinetic Indices for Salicylate at Steady-State (Day 9) 2 x 650 mg q 8 h 2 x 325 m~ q4h 0 - 8 hr AUC (mcg-hrs/mL)902.35 + 456.88* 510,26 + 227.46 max (mcg/mL) 128.00 + 60.54* 83.81 + 33.20 Tmax (hours) 3.08 + 1.51 3.42 + 1.88 t 1/2 (hours) 10.15 + 5.38* 5.00 + Z.37~
el (hours 1)1) o.og + 0.04* 0.17 + 0.09 * Statistically different at the 5~O level or greater.
^ Calculation on numbers after second dose.
1) Elimination constant Relative 0 - 8 hr AUC (~) 177.26 + 57.61 Relative Cmax (%) 153.18 + 47.92 1 3 ~2809 Evaluation of results Statistical evaluation of steady-state plasma salicylate concentrations usina appropriate statistical tests (paired t-tests) showed significantly higher plasma concentrations for the Example 2 formulation at every time point. The in-crease in plasma free salicylate levels is greater than predicted even if a 3.9 gram dose of the reference formula-tion had been administered. Statistical evaluation showed that the mean 0-8 hours AUC and mean Cmax were significantly higher for the Example 2 formulation. Adjustment of the mean 0-8 hour AUC to a 3.9 g/dose for each product provides an estimated relative bioavailability of the Example 2 formula-tion of the invention of 147 per cent that of the reference product. The Example 2 formulation of the invention showed a significantly longer half-life and smaller Kel.
The total salicylate concentration in urine was measured over 24 hours on day 9. Values obtained for the Example 2 formulation were 1488.42 + 531.08 mg and for the reference formulation 1265.97 + 572.16 mg. These values are similar.
_15- 100-6970 1 3s280q Trial B:
Steady-State Bioavailability of 1300 mg ASA according to the invention administered twice a day The Example 2 formulation (650 mg ASA tablet) was admini-stered at a dose of 2 tablets to 6 healthy male volunteers. 3 of whom had completed the previous trial A at 7 am and 7 pm for 8 days with a final dose at 7 am on day 9. The total daily dose of ASA was 2~6 gOThe protocol was the same as that discussed above except for the lower dose.
Statistical evaluation on day 8 and day 9 indicated that the steady state had been achieved by day 9.
The results obtained up to 12 hours after drug administration are given below:
Day 9 (Steady-State) Mean Plasma Salicylate Conc. (mcg/mL) Sampling Time Example 2 (hour) 2 x 650 mg ql2h 0 49.70 + 21.16 1.0 54.82 + 22.75 2.0 58.72 + 22.53 3.0 62.19 + 23.31 4.0 59.90 + 23.18 5.0 55087 + 25.84 6.0 55.18 + 22.04 8.0 47~22 + 24.77 10.0 42.98 + 24.19 12.0 34.72 + 20.09 1 332~0q The 0 - 8 hour AUC was calculated as 446 + 182.46 mcg-hours/
ml. Cmax was 64.11 + 21,78 (mcg/ml).
The results indicate that the dose of 2.6 9 ASA gi ven as a dose of 1 300 mg ASA twice a day in a formulation according ~the invention provides comparable plasma free salicylate levels to the immediate release formulation at a dose of 3025 9 ASA given as a dose of 650 mg ASA five times a day.
Urine total SA concentrations are also measured over a 24 hour periodO The cumulative total SA was 1322 + 162 mg.
This value is similar to the values found in Trial A.
These results suggest that at high doses of ASA at which an anti-inflammatory effect occurs there is a constant satu-ration of metabolic pathways (as indicated by the dose-in-dependent cumulative urinary excretion values). We have found that the plasma concentration of free SA increases dispro-portionately to the dose at high doses of ASA. We believe that this may be due to a combination of the effect of clearance of the unbound ASA and the ratio of protein-bound SA to unbound SA in plasma. When metabolism is saturable clearance should decrease but when protein binding is saturated clearance increases. Therefore the steady state concentration of free SA may depend on the magnitude of each of these two effects.
The pharmaceutical compositions of the invention have a longer elimination half life (e.g. greater than 9 hours) than that of immediate release ASA pharmaceutical compositions. In the case of immediate release ASA compositions large peak-to-trough ratios of free SA may occur which may provide periods of in-creased metabolism of SA resulting in lower steady state levels.
The pharmaceutical compositions of the invention on the other hand provide therapeutic concentrations of SA at lower daily doses than immediate release ASA pharmaceutical compositions.
and have less GI-irritating potential.
1 3 280q The pharmaceutical compositions of the invention may be administered for all indications that ASA is indicated for~
in particular pains of rheumatism, arthritis, lumbago, neuralgia, neuritis, sciatica and bursitis (anti-inflammatory indications)~ fever and cerebral ischemic attacks.
~or anti-inflammatory indications a dose of about 600 to 1300, e.g. 650 to 1300 mg, ASA every 8 to 12 hours is satis-factory~ Daily doses contemplated are from about 2.6 to about 3.9 9. Analgesic and anti-pyretic indicated doses are from about 300 to about 700 mg, e.g. 325 to 650 mg. For rheumatic fever daily doses of 100 mg ASA/kg body weight may be given in divided doses every 8 to 12 hours to counter-act pain, swelling and fever. For cerebral ischemic attacks an indicated dose is 650 mg every 12 hours.
In another aspect the present invention provides an oral solid pharmaceutical composition comprising at least 300 mg acetyl-salicylic acid in sustained release form and capable of providing in the steady state on administration of an acetylsalicylic acid daily dose of 2.6 9 in divided doses 2 or 3 times a day a si~nifi-cantly higher blood plasma free salicylic acid concentration than that obtained on administration of immediate release acetylsali-cylic acid tablets given at the same daily dose in divided doses every 4 hours.
Conveniently the pharmaceutical composition contains 300 to 700 mg ASA and has dissolution rate at 37 C in water of from 15 to 40 per cent in 1 hour and not less than 70 9O/ at 8 hours.
Prefera~ly in 1 hour from 20 to 35 per cent is released.
Conveniently at 8 hours from 70 to 90 per cent eOg. 80 to 90 per cent is releasedO
- 1 3S280~ 100-6970 The following examples illustrate the invention.
In the Examples:
Microcrystalline cellulose has a molecular weight of from 30,000 to 50,000: ~mean particle size 30-100 microns; specific gravity 1055; tap volume 0.30 to 0.80~ The material used was the brand Avicel PH 102 (Registered Trade Mark) available from FMC Corporation, Marcus Hook, USA. It complies with specifications given for microcrystalline cellulose in USP/National Formulary XXI.
Hydroxypropyl methylcellulose 2208 has a number average molecular weight of 120,000; viscosity approx. 15,000 cps:
a 19-24 per cent hy weight methoxyl content and a 4-12 per cent by weight hydroxypropyl content. Used was brand Methocel K15M Premuim (Registered Trade Mark) available from Dow Chemical Company Michigan USA. It complies with specifications given for hydroxypropyl methylcellulose 2208 in USP XXI.
Pregelatinized Starch is a modified corn starch and comprises 5 per cent amylose, 15 per cent amylopectin and 80 per cent unmodified corn starch. It is partially cold water soluble.
The material used was the brand Starch 1500 (Registered Trade Mark) available from Colorcon Inc., West Point, Pennsylvania.
USA. It complies with the specifications given for pregela-tinized starch in USP / National Formulary XXI.
Colloidal silicon dioxide was the brand Cab-0-Sil (Registered Trade Mark) available from Cabot Corporation, Boston, Mass.USA.
It complies with the specifications given in USP/~National Formulary XXI.
The ASA used are 40 mesh crystals. The immediate release for-mulation used as reference in the bioavailability trials was brand Bayer Aspirin (Registered Trade Mark).
3 .S 2 ~ O q Further specifications for the above products are available in Manufacturer's brochures and in Lexikon der Hilfsstoffe by H.P.Fiedler. Second Edition 1981~ Editio Cantor~Aulen-dorf, WOGermanyO
All other ingredients used meet the specifications laid down by the USP XXIo 1 3s280~
EXAMPLE 1: 325 m~ ASA tablets __.___ ____ _ _____ mg/tahlet ASA 325.000 Microcrystalline cellulose 47.500 Hydroxypropyl methylcellulose 27.625 Pregelatinized Starch 22.100 Stearic Acid 2.125 Colloidal Silicon Dioxide 0.650 A charge to make up 1 million tablets is made up as follows:-The above quantities are multipled by 1 million,e.g. 325 kgacetylsalicylic acid are used. 50 kg of acetylsalicylic acid are mixed with the silicon dioxide. The remaining acetylsali-cylic acid, hydroxypropyl methylcellulose, silicon dioxide/
acetylsalicylic acid mixture, microcrystalline cellulose and pregelatinized starch are introduced in an alternating fashion into a 30 cubic feet twin shell blender. Mixing is effected for 15 minutes. 40 kg of the mixture is removed. The remaining mixture is passed through a 20 mesh (aperture size 1.00 mm ;
wire diameter 0.63 mm) stainless steel screen on an oscilla-ting granulator~ The 40 kg unscreened mixture and the stearic acid are mixed for 5 minutes, screened through a 20 mesh stain-less steel screen as described above with an oscillating granu-lator, and mixed ~ith the previously screened mixture. Mixing is effected.for 15 minutes using a tumbling action to produce a granulate. The granulate is then tabletted on a rotary tablet press. Tablet weight 425 mg. Thickness 4.68 - 4.85 mm. Hardness 8-12 Kiloponds (Heberlein method).
Dissolution release data (average of 6 tablets) in water at 37C:
Per cent release of ASA
Lot 1 Lot 2 1 hour 23.1 30.3 2 hour 39.4 45.4 3 hour 51.2 57.0 4 hour 61.4 65.9 6 hour 72.5 76.5 8 hour 80.7 &6.6 12 hour 87.1 93.6 EXAMPLE 2: 650 m~ ASA tablets In analogous manner to that disclosed in Example 1 are pro-duced tahlets each containing:
mg/tablet ASA 650.000 Microcrystalline cellulose 95.000 Hydroxypropyl methylcellulose55.25 Pregelatinized Starch 44.20 Stearic Acid 4.25 Colloidal Silicon Dioxide 1.30 The batch size is for 500,000 tablets. The resultant tablets have a weight each of 850 mg and thi-ckness 6.25 to 6.40 mm.
~issolution release date (average of 6 tablets) in water at 37~C:-Per cent release of ASA
Lot 1 Lot 2 1 hour 21.5 26.8 2 hour 34.4 39.9 3 hour 44.2 49.8 4 hour 53-4 57-7 6 hour 66.1 69.0 8 hour 75.7 77.1 12 hour 86.9 85.7 -12- 10~-6970 1 ~32809 Trial A:
Steady State Bioavailability of 1300 mg ASA according to the i~nvention administered 3 times a day The pharmaceutical composition of the invention described in example 2 (650 mg ASA tablet) was administered at a dose of 2 tablets to 12 healthy male volunteers at 7 am, 3 pm and 11 pm on days 1 to 8 and at 7 am on day 9. The total daily dose was 3.9 9 ASA.
An immediate release formulation was given at a dose of 325 mg tablets every 4 hours from 7 am to 11 pm on days 1 to 8 and at 7 am and 11 am on day 9. The total daily dose was 3~25 9 ASA.
Each subject received the two formulations in a 9 day study session according to a random sequence. The wash-out period at the end of the study session was 6 days.
Blood samples were obtained on day 8 at 7 am (pre-dose) and 11 am (pre-dose) and on day 9 at 7 am (pre-dose) and 1, 2, 3, 4 (pre-dose in the case of the immediate release formu-lation), 5, 6, 8, 10 and 12 hours following drug administra-tion at 7 am.
Statistical evaluation for both formulation on days 8 and 9 indicated that both were at the steady state for the day 9 bioavailability study.
The results obtained for the measurement of free plasma salicylate in the blood were as follows (REFERENCE = imme-diate release formulation):-_13_ 100-6970 1 3 ~2809 Results:
Day 9 (Steady-State) Mean Plasma Salicylate Concentrations (mcglmL) 3.9 G/day 3.25 G/day Sampling Time EXAMPLE 2 REFERENCE
(hour) 2 x 650 mg q8h 2 x 325 mg q4h 0 113.90 + 56.14* 56.29 + 36.90 1.00 117.91 + 56.02* 68.55 + 37.07 2.00 114.17 + 57.27* 72.53 + 31.12 3.00 118.58 + 61.07* 68.54 + 39.81 4O00 117015 + 59.25* 54.49 + 32.29 5.00 115.66 + 58.85* 67.02 + 27.50 6000 111082 + 57.34* 64.28 + 21.55 8.00 94.20 + 57.19* 54.57 + 29.53 10.00 82.82 + 49.36* 41.94 + 26.46 12000 68.11 + 52007* 30.02 + 23.23 * The two formulations differ statistically at the 5 level or greater.
Pharmacokinetic Indices for Salicylate at Steady-State (Day 9) 2 x 650 mg q 8 h 2 x 325 m~ q4h 0 - 8 hr AUC (mcg-hrs/mL)902.35 + 456.88* 510,26 + 227.46 max (mcg/mL) 128.00 + 60.54* 83.81 + 33.20 Tmax (hours) 3.08 + 1.51 3.42 + 1.88 t 1/2 (hours) 10.15 + 5.38* 5.00 + Z.37~
el (hours 1)1) o.og + 0.04* 0.17 + 0.09 * Statistically different at the 5~O level or greater.
^ Calculation on numbers after second dose.
1) Elimination constant Relative 0 - 8 hr AUC (~) 177.26 + 57.61 Relative Cmax (%) 153.18 + 47.92 1 3 ~2809 Evaluation of results Statistical evaluation of steady-state plasma salicylate concentrations usina appropriate statistical tests (paired t-tests) showed significantly higher plasma concentrations for the Example 2 formulation at every time point. The in-crease in plasma free salicylate levels is greater than predicted even if a 3.9 gram dose of the reference formula-tion had been administered. Statistical evaluation showed that the mean 0-8 hours AUC and mean Cmax were significantly higher for the Example 2 formulation. Adjustment of the mean 0-8 hour AUC to a 3.9 g/dose for each product provides an estimated relative bioavailability of the Example 2 formula-tion of the invention of 147 per cent that of the reference product. The Example 2 formulation of the invention showed a significantly longer half-life and smaller Kel.
The total salicylate concentration in urine was measured over 24 hours on day 9. Values obtained for the Example 2 formulation were 1488.42 + 531.08 mg and for the reference formulation 1265.97 + 572.16 mg. These values are similar.
_15- 100-6970 1 3s280q Trial B:
Steady-State Bioavailability of 1300 mg ASA according to the invention administered twice a day The Example 2 formulation (650 mg ASA tablet) was admini-stered at a dose of 2 tablets to 6 healthy male volunteers. 3 of whom had completed the previous trial A at 7 am and 7 pm for 8 days with a final dose at 7 am on day 9. The total daily dose of ASA was 2~6 gOThe protocol was the same as that discussed above except for the lower dose.
Statistical evaluation on day 8 and day 9 indicated that the steady state had been achieved by day 9.
The results obtained up to 12 hours after drug administration are given below:
Day 9 (Steady-State) Mean Plasma Salicylate Conc. (mcg/mL) Sampling Time Example 2 (hour) 2 x 650 mg ql2h 0 49.70 + 21.16 1.0 54.82 + 22.75 2.0 58.72 + 22.53 3.0 62.19 + 23.31 4.0 59.90 + 23.18 5.0 55087 + 25.84 6.0 55.18 + 22.04 8.0 47~22 + 24.77 10.0 42.98 + 24.19 12.0 34.72 + 20.09 1 332~0q The 0 - 8 hour AUC was calculated as 446 + 182.46 mcg-hours/
ml. Cmax was 64.11 + 21,78 (mcg/ml).
The results indicate that the dose of 2.6 9 ASA gi ven as a dose of 1 300 mg ASA twice a day in a formulation according ~the invention provides comparable plasma free salicylate levels to the immediate release formulation at a dose of 3025 9 ASA given as a dose of 650 mg ASA five times a day.
Urine total SA concentrations are also measured over a 24 hour periodO The cumulative total SA was 1322 + 162 mg.
This value is similar to the values found in Trial A.
Claims (28)
1. A process for the production of an acetylsalicylic acid containing sustained release pharmaceutical composition which comprises mixing acetylsalicylic acid and a) microcrystalline cellulose and b) hydroxypropyl methylcellulose wherein the weight ratio of a) to b) is at least 1 to 1 and c) pregelatinized starch.
2. A process for the production of an acetylsalicylic acid containing sustained release pharmaceutical composition which comprises mixing acetylsalicylic acid and a) microcrystalline cellulose and b) hydroxypropyl methylcellulose wherein the weight ratio of a) to b) is at least 1 to 1 and tabletting the resulting mass.
3. A process according to claim 1 or 2 wherein tablet unit dosage forms are produced containing from 300 to 700 mg acetylsalicylic acid.
4. An acetylsalicylic acid containing sustained release pharmaceutical composition comprising acetylsalicylic acid in admixture with a) microcrystalline cellulose and b) hydroxypropyl methylcellulose wherein the weight ratio of a) to b) is at least 1 to 1 and c) pregelatinized starch.
5. A composition according to claim 4 in the form of a tablet.
6. An acetylsalicylic acid containing sustained release pharmaceutical composition comprising acetylsalicylic acid in admixture with a) microcrystalline cellulose and b) hydroxypropyl methylcellulose wherein the weight ratio of a) to b) is at least 1 to 1 and the composition is in the form of a tablet.
7. A composition according to claim 6 containing pregelatinized starch.
8. A composition according to claim 5 wherein the amount of acetylsalicylic acid per tablet is from 300 to 700 mg.
9. A composition according to claim 8 wherein the amount of acetylsalicylic acid is 325 or 650 mg.
10. A composition according to claim 4, 5, 6, 7, 8 or 9 wherein the microcrystalline cellulose has a mean polymerisation number of from about 200 to 2000.
11. A composition according to claim 4, 5, 6, 7, 8 or 9 wherein the mean molecular weight of the microcrystalline cellulose is from about 20,000 to 100,000.
12. A composition according to claim 4, 5, 6, 7, 8 or 9 wherein the mean molecular weight of the microcrystalline cellulose is from 30,000 to 50,000.
13. A composition according to claim 4, 5, 6, 7, 8 or 9 wherein the particle size of the microcrystalline cellulose is from 5 to about 140 microns.
14. A composition according to claim 4, 5, 6, 7, 8 or 9 wherein the methoxy content of the hydroxypropyl methylcellulose is from about 15 to about 34 percent by weight.
15. A composition according to claim 4, 5, 6, 7, 8 or 9 wherein the methoxy content of the hydroxypropyl methylcellulose is from 19 to 24 percent by weight.
16. A composition according to claim 4, 5, 6, 7, 8 or 9 wherein the hydroxypropyl content of the hydroxypropyl methylcellulose is from about 4 to about 32 percent by weight.
17. A composition according to claim 4, 5, 6, 7, 8 or 9 wherein the hydroxypropyl content of the hydroxypropyl methylcellulose is from about 4 to 12 percent by weight.
18. A composition according to claim 4 wherein the viscosity of the hydroxypropyl methylcellulose is about 15 to about 50,000 cps (based on a 2 percent by weight aqueous solution at 20 degrees centigrade).
19. A composition according to claim 18 wherein the viscosity of the hydroxypropyl methylcellulose is 4000 to 50,000 cps.
20. A composition according to claim 4, 5, 6, 7, 8, 9, 18 or 19 wherein the mean molecular weight of the hydroxypropyl methylcellulose is from about 20,000 to 200,000.
21. A composition according to claim 4, 5, 6, 7, 8, 9, 18 or 19 wherein the mean molecular weight of the hydroxypropyl methylcellulose is 90,000 to 130,000.
22. A composition according to claim 4, 5, 6, 7, 8, 9, 18 or 19 wherein the weight ratio of microcrystalline cellulose to hydroxypropyl methylcellulose is from 10:1 to 1:1.
23. A composition according to claim 4, 5, 6, 7, 8, 9, 18 or 19 wherein the weight ratio of microcrystalline cellulose to hydroxypropyl methylcellulose is from 3:1 to 1:1.
24. A composition according to claim 4, 5, 6, 7, 8, 9, 18 or 19 wherein the weight ratio of microcrystalline cellulose to acetylsalicylic acid is from 1:5 to 1:10.
25. A composition according to claim 4, 5, 6, 7, 8, 9, 18 or 19 wherein the weight ratio of microcrystalline cellulose to acetylsalicylic acid is from 1:6 to 1:7.5.
26. A composition according to claim 4, 5, 6, 7, 8, 9, 18 or 19 wherein the weight ratio of pregelatinized starch to hydoxypropyl methylcellulose is from about 1:1 to about 1:5.
27. A composition according to claim 4, 5, 6, 7, 8, 9, 18 or 19 wherein the weight ratio of acetylsalicylic acid to all other excipients present is from 2:1 to 4:1.
28. A composition according to claim 4, 5, 6, 7, 8, 9, 18 or 19 in the form of a tablet compressed to a hardness of about 8 to 12 kiloponds.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB868624213A GB8624213D0 (en) | 1986-10-09 | 1986-10-09 | Sustained release pharmaceutical compositions |
| GB8624213 | 1986-10-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1332809C true CA1332809C (en) | 1994-11-01 |
Family
ID=10605478
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000548872A Expired - Lifetime CA1332809C (en) | 1986-10-09 | 1987-10-08 | Sustained release pharmaceutical compositions |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JPS63101334A (en) |
| KR (1) | KR880004801A (en) |
| AU (1) | AU7942087A (en) |
| BE (1) | BE1000732A5 (en) |
| CA (1) | CA1332809C (en) |
| CH (1) | CH675831A5 (en) |
| DE (1) | DE3733540A1 (en) |
| DK (1) | DK527487A (en) |
| ES (1) | ES2014518A6 (en) |
| FI (1) | FI874414A (en) |
| FR (1) | FR2604902B1 (en) |
| GB (2) | GB8624213D0 (en) |
| GR (1) | GR871550B (en) |
| HU (1) | HU201875B (en) |
| IL (1) | IL84104A0 (en) |
| IT (1) | IT1221493B (en) |
| LU (1) | LU87009A1 (en) |
| NL (1) | NL8702294A (en) |
| NO (1) | NO874200L (en) |
| NZ (1) | NZ222083A (en) |
| PH (1) | PH24227A (en) |
| PT (1) | PT85880B (en) |
| SE (1) | SE8703889L (en) |
| ZA (1) | ZA877617B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5948437A (en) * | 1996-05-23 | 1999-09-07 | Zeneca Limited | Pharmaceutical compositions using thiazepine |
| US5895663A (en) * | 1997-07-31 | 1999-04-20 | L. Perrigo Company | Pseudoephedrine hydrochloride extended-release tablets |
| EE05022B1 (en) * | 1999-03-31 | 2008-06-16 | Janssen Pharmaceutica N.V. | Use of Pregelatinised Starch in a Hydrophilic Controlled Release Preparation and a Hydrophilic Controlled Release Preparation |
| US6242003B1 (en) | 2000-04-13 | 2001-06-05 | Novartis Ag | Organic compounds |
| US20060127474A1 (en) | 2001-04-11 | 2006-06-15 | Oskar Kalb | Pharmaceutical compositions comprising fluvastatin |
| SE0102887D0 (en) * | 2001-08-29 | 2001-08-29 | Astrazeneca Ab | New formulation |
| SE0102886D0 (en) * | 2001-08-29 | 2001-08-29 | Astrazeneca Ab | New formulation |
| SE0102888D0 (en) * | 2001-08-29 | 2001-08-29 | Astrazeneca Ab | New formulation |
| TWI338583B (en) | 2004-05-20 | 2011-03-11 | Otsuka Pharma Co Ltd | Solid pharmaceutical formulation |
| ES2330227T3 (en) * | 2004-09-09 | 2009-12-07 | Psicofarma, S.A. De C.V. | PHARMACEUTICAL COMPOSITION OF PROLONGED HYDRALAZINE RELEASE AND ITS USE AS SUPPORT FOR CANCER TREATMENT. |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE795766A (en) * | 1972-02-22 | 1973-08-22 | Lilly Co Eli | PROPOXYPHENE DELAY NAPSYLATE PARTICLES AND PROCESS FOR MANUFACTURING SUCH PARTICLES |
| US4389393A (en) * | 1982-03-26 | 1983-06-21 | Forest Laboratories, Inc. | Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose |
| US4520009A (en) * | 1983-11-28 | 1985-05-28 | Verex Laboratories, Inc. | Sustained released aspirin formulation |
| DE3346571A1 (en) * | 1983-12-23 | 1985-07-04 | Bayer Ag, 5090 Leverkusen | ORAL RETARDED ACETYLSALICYL ACID FORMULATIONS |
| AU4064285A (en) * | 1984-03-21 | 1985-10-11 | American Home Products Corporation | Sustained release pharmaceutical capsules |
-
1986
- 1986-10-09 GB GB868624213A patent/GB8624213D0/en active Pending
-
1987
- 1987-09-25 NL NL8702294A patent/NL8702294A/en not_active Application Discontinuation
- 1987-09-25 HU HU874311A patent/HU201875B/en not_active IP Right Cessation
- 1987-10-02 FR FR878713759A patent/FR2604902B1/en not_active Expired - Lifetime
- 1987-10-02 CH CH3838/87A patent/CH675831A5/de not_active IP Right Cessation
- 1987-10-02 BE BE8701131A patent/BE1000732A5/en not_active IP Right Cessation
- 1987-10-03 DE DE19873733540 patent/DE3733540A1/en not_active Withdrawn
- 1987-10-06 LU LU87009A patent/LU87009A1/en unknown
- 1987-10-06 IL IL84104A patent/IL84104A0/en unknown
- 1987-10-06 KR KR870011168A patent/KR880004801A/en not_active Application Discontinuation
- 1987-10-07 PT PT85880A patent/PT85880B/en not_active IP Right Cessation
- 1987-10-07 NZ NZ222083A patent/NZ222083A/en unknown
- 1987-10-07 GB GB8723515A patent/GB2195893B/en not_active Expired - Lifetime
- 1987-10-07 AU AU79420/87A patent/AU7942087A/en not_active Abandoned
- 1987-10-07 FI FI874414A patent/FI874414A/en not_active IP Right Cessation
- 1987-10-07 GR GR871550A patent/GR871550B/en unknown
- 1987-10-07 NO NO874200A patent/NO874200L/en unknown
- 1987-10-08 DK DK527487A patent/DK527487A/en not_active Application Discontinuation
- 1987-10-08 SE SE8703889A patent/SE8703889L/en not_active Application Discontinuation
- 1987-10-08 PH PH35906A patent/PH24227A/en unknown
- 1987-10-08 CA CA000548872A patent/CA1332809C/en not_active Expired - Lifetime
- 1987-10-08 JP JP62256149A patent/JPS63101334A/en active Pending
- 1987-10-08 IT IT48469/87A patent/IT1221493B/en active
- 1987-10-08 ES ES8702873A patent/ES2014518A6/en not_active Expired - Lifetime
- 1987-10-09 ZA ZA877617A patent/ZA877617B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU7942087A (en) | 1988-04-14 |
| SE8703889L (en) | 1988-04-10 |
| CH675831A5 (en) | 1990-11-15 |
| PH24227A (en) | 1990-05-04 |
| DK527487D0 (en) | 1987-10-08 |
| BE1000732A5 (en) | 1989-03-21 |
| IT8748469A0 (en) | 1987-10-08 |
| NO874200L (en) | 1988-04-11 |
| DK527487A (en) | 1988-04-10 |
| GB8624213D0 (en) | 1986-11-12 |
| SE8703889D0 (en) | 1987-10-08 |
| JPS63101334A (en) | 1988-05-06 |
| HU201875B (en) | 1991-01-28 |
| NO874200D0 (en) | 1987-10-07 |
| ES2014518A6 (en) | 1990-07-16 |
| PT85880A (en) | 1987-11-01 |
| NL8702294A (en) | 1988-05-02 |
| GB8723515D0 (en) | 1987-11-11 |
| ZA877617B (en) | 1989-05-30 |
| NZ222083A (en) | 1991-05-28 |
| IL84104A0 (en) | 1988-03-31 |
| LU87009A1 (en) | 1988-05-03 |
| FI874414A0 (en) | 1987-10-07 |
| HUT52958A (en) | 1990-09-28 |
| IT1221493B (en) | 1990-07-06 |
| FR2604902B1 (en) | 1991-04-26 |
| GB2195893A (en) | 1988-04-20 |
| GR871550B (en) | 1988-02-15 |
| KR880004801A (en) | 1988-06-27 |
| FR2604902A1 (en) | 1988-04-15 |
| PT85880B (en) | 1990-07-31 |
| GB2195893B (en) | 1991-05-08 |
| DE3733540A1 (en) | 1988-04-14 |
| FI874414A (en) | 1988-04-10 |
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