AU618748B2 - Pellets with enzymatically controlled drug release - Google Patents

Pellets with enzymatically controlled drug release Download PDF

Info

Publication number
AU618748B2
AU618748B2 AU21245/88A AU2124588A AU618748B2 AU 618748 B2 AU618748 B2 AU 618748B2 AU 21245/88 A AU21245/88 A AU 21245/88A AU 2124588 A AU2124588 A AU 2124588A AU 618748 B2 AU618748 B2 AU 618748B2
Authority
AU
Australia
Prior art keywords
enzyme
pharmaceutical
composition according
substance
pharmaceutical substance
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.)
Ceased
Application number
AU21245/88A
Other versions
AU2124588A (en
Inventor
Jorn Ullrich Becker
Horst-Georg Zerbe
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Riker Laboratories Inc
Original Assignee
Riker Laboratories Inc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Riker Laboratories Inc filed Critical Riker Laboratories Inc
Publication of AU2124588A publication Critical patent/AU2124588A/en
Application granted granted Critical
Publication of AU618748B2 publication Critical patent/AU618748B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1664—Compounds of unknown constitution, e.g. material from plants or animals
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Botany (AREA)
  • Zoology (AREA)
  • Medicinal Preparation (AREA)

Description

h AU-AI-21245/88 WT INT LEb AL ERT ORG ZATION INTERNATIONAL APPLICATION PUBISH U DER TE ENT COOPERATION TREATY (PCT) (51) International Patent Classification 4: (11) International Publication Number: WO 89/ 00045 A61K 9/22, 47/00, 37/48 Al (43) International Publication Date: 12 Jantrary 1989 (12.01.89) (21) International Application Number: PCT/US88/02131 (74) Agents: SPRAGUE, Robert, W. et al.; Minneso'a Mining and Manufacturing Company, P.O. Box 33427, (22) International Filing Date: 23 June 1988 (23.06.88) Saint Paul, MN 55133-3427 (US).
(31) Priority Application Number. P 37 21 574.4 (81) Designated States: AT (European patent), AU, BE (European patent), CH (European patent), DE (Euro- (32) Priority Date: 30 June 1987 (30.06.87) pean patent), DK, FR (European patent), GB (European patent), IT (European patent), JP, LU (Euro.
(33) Priority Country: Dc pean patent), NL (European patent), NO, SE (European patent).
(71)Applicant: RIKER LABORATORIES, INCORPO- RATED [US/US]; Building 225-1N-07, 3M Center, Published Saint Paul, MN 55144-1000 With international search report.
Before the expiration of the time limit for amending the (72) Inventors: ZERBE, Horst-Georg BECKER, Jorn, UII- claims and to be republished in the event of the receipt rich Kettelhack Riker Pharma GmbH, Wilbecke of amendments.
12-14, P.O. Box 1340, D-4280 Borken 1 (DE).
A 23 MAR 1989
AUSTRALIAN
3 0 JAN1989 PATENT OFFICE (54) Title: PELLETS WITH ENZYMATICALLY CONTROLLED DRUG RELEASE (57) Abstract Pharmaceutical compositions in pellet form with enzymatically controlled release of the pharmaceutical substance are described which comprise a core and an envelope layer surrounding said core. The core contains the pharmaceutical substance, an enzyme and a substrate for the enzyme. The envelope layer cc.atains a water-insoluble film-forming macrom.
olecular substance and a water-solubb' pore former, WYO 89/00045 PCT/US88/02131
-I-
PELLETS WITH ENZYMATICALLY CONTROLLED DRUG RELEASE Field of the Invention The present invention relates to a harmaceutical composition in pellet form with enzymatically controlled release of the pharmaceutical substance.
Background of the Invention In many cases, pharmaceutical substances are administered to patients as pharmaceutical compositions with so-called sustained release. After the patient has taken the pharmaceutical composition, the pharmaceutical substance is released in the gastro-intestinal tract slowly over several hours.' n this way, the frequency of administration of the pharmaceutical composition, which in many cases the patient considers annoying, can be reduced.
At the same time, the sustained release of the pharmaceutical substance prevents plasma level peaks and undesired side effects may zesult from fast resorption.
The sustained release of the pharmaceutical substance can be achieved for instance by mixing the pharmaceutical substance with a water-insoluble carrier and compressing it into tablets. Suitable cdrrier materials are cellulose derivatives, waxes, synthetic materials, such as polyvinylchloride, polyvinylacetate, polyethylene or differently substituted polymethacrylic acid derivatives.
Other water-insoluble polymers are known to the expert.
The release of the pharmaceutical substance can also be retarded by mixing the pharmaceutical substance with hydropnilic macromolecules and compressing the mixture into tablets. Such substances are also known to the expert.
WO 89/00045 PCT/US88/02131 -2- Examples are gum arabic, cellulose derivatives, water-soluble polyacrylic acid derivatives, polyvinyl pyrrolidone, tragacanth or guar.
In both cases so called matrix systems are produced, from which the pharmaceutical substance, after having been administered to the patient, is released under controlled diffusion. The degree to which the release of the pharmaceutical substance is retarded essentially i0 depends on the quantitative ratio of the pharmaceutical substance and the polymer forming the matrix.
In another method known to the expert, the tablets, pellets or granules containing the pharmaceutical substance are coated with a lacquer layer of a film-forming material that is insoluble in the gastric juice. The corresponding film formers are known to the expert.
Examples ci preferred film formers are ethyl cellulose, polyvinylacetate, anionic polymers of methacrylic acid and methacrylic acid esters, acrylic and methac ylic acid ester copolymers, such as 1:1 methacrylic acid/methacrylate copolymers and 2:1 ethylacrylate/methylmethacrylate copolymers, shellac or mixtures of these substances. The film may additionally contain pore-forming substances which are likewise known to the expert. Polyethylene glycols, polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose or mixtures of these substances are preferred. The type and amount of these additives depends on the rate at which the pharmaceutical substance is to be released.
All foregoing systems suffer from the disadvantage that once the patient has taken the 1 pharmaceutical composition, the release rate of the pharmaceutical substance is subject to greater or smaller variations depending on the viscosity of the gastro-intestinal content, the peristalsis or the pH value.
This may, for instance, have as a consequence that the WO 89/00045 PCT/US88/02131 -3necessary blood level is not achieved and thus the desired therapeutic effect is not attained or that plasma level peaks are produced which may entail undesired side effects.
The release of the pharmaceutical substance independently from the aforementioned physiological influences can be achieved by release systems in which the release of the pharmaceutical substance is osmotically controlled. US Patent 3,916,899, for instance, describes a preparation (Osmogit) consisting of two compartments separated by a semipermeable membrane, one of these compartments being filled with an osmotically active agent such as potassium chloride and the other compartment containing the pharmaceutical substance. After the preparation has been administered to the patient, gastro-intestinal fluid diffuses into the compartment containing the osrmotically active agent, whereby the solution of the pharmaceutical substance is pressed into the gastro-intestinal tract by a specific opening provided for this purpose. Other embodiments of this preparation are described in US Patents 4,612,008, 4,503,030, 4,210,139 and DE-OS 33 10 096. However, the fact that after administration a highly concentrated solution of tie< osmotically active agent is pressed through the opening, which may cause quite some side effects such as perforations of the patient's intestinal wall, constitutes a considerable disadvantage of this preparetion. This is known as the so-called "cutting torch" effect.
A further disadvantage of this preparation is that it is in the "single-unit" form. As such its duration of stay in the portions of the gastro-intestinal tract which are capable of absorption depends to a large degree on the individual variations in the passage times of the gastrointestinal tract. In the case of a reduced passage time, the duration of the pharmaceutical compositions in those portions \of the intestine which are capable of absorption is shortened so that a considerable part of the pharmaceutical substance is discharged unused.
WO 89/00045 PCT/US88/02131 -4- US Patent 3,493,652 describes the use in pharmaceutical compositions of a substrate and an enzyme disintegrating the substrate. The pharmaceutical substance is closely surrounded by the substrate which is a carbohydrate, lipid or protein whereby the release of the pharmaceutical substance is prevented. The enzyme causes the matrix to disintegrate and thus allows the pharmaceutical substance to dissolve in the gastro-intestinal juice. The structure and the principle of operation of the invention disclosed in US Patent 3,493,652, however, in the case of orally administered solid pharmaceutical compositions described therein, have the consequence that the rate of release of the incorporated pharmaceutical substance continues to depend on physiological influences, such as viscosity of the intestinal content and intestinal peristalsis, and thus may be subject to considerable individual variations.
Summary of the Invention The technical problem underlying the present invention is to provide a pharmaceutical composition in pellet form comprising a core, which core contains the pharmaceutical substanice, and an envelope layer surrounding the core, which minimizes the influence of the physiological factors, such as intestinal peristalsis and the. viscosity of the intestinal content, on the release of the active ingredient and at the same time balances 3 c -ndividual variations of the gastro-ntestinal pa age times. The problem is solved in that a) the ore contains the pharmaceutical substance or a mixt of pharmaceutical substances, a pharmacologically eptable enzyme or enzyme mixture and a pharmacologic y acceptable polymer as a Sfiller and substrate the enzyme or enzyme mixture, and b) the envelope yer contains a pharmacologically acceptabl water-i!isoluble, film-forming macromolecular sub nce and a water-cl l i lI nr-fnrm- r w tel-shlp nnPfnrmer -4aindividual variations of the gastro-intestinal passage times.
Accordingly, the present invention provides a pharmaceutical composition in pellet form comprising a core, which core contains the pharmaceutical substance, and an envelope layer surrounding the core, the composition being characterized in that the core contains the pharmaceutical substance or a mixture of pharmaceutical substances, a pharmacologically acceptable enzyme or enzyme mixture, a pharmacologically acceptable polymer as a filler and as a substrate for the enzyme or enzyme mixture, and the envelope layer contains a pharmacologically acceptable, water-insuluble, film-forming I, macromolecular substance and a water-soluble p pore former.
i V e i o o* L i r~ ti i WO 89/00045 PCT/US88/02131 After administration, the pellets disperse over the gastroinestinal content, whereby the individual variations of the gastro-intestinal passage times are compensated for.
Apart from the pharmaceutical substance or mixture of pharmaceutical substances and optionally additional auxiliaries, the core contains in simple mixture a pharmaceutically acceptable polymer as a filler and substrate, and an enzyme or enzyme mixture for disintegrating said polymer. The envelope layer contains a pharmacologically acceptable water-insoluble, film-forming macromolecular substance and a water-soluble pore-former.
In order to facilitate administration to the patient, the pellets are preferably filled into hard gelatin capsules of a suitable size. The purpose behind this pharmaceutical composition is that after the composition has been taken by the patient and come into contact with the gastro-intestinal fluid, the polymer is enzymatically decomposed into pharmaceutically acceptable degradation products (water-soluble subunits) which are dissolved by the gastro-intestinal juice. The increase in the osmotic pressure thus produced in the interior of the pellets rasults in a continuous flow of the solution of the pharmaceutLcal substance from the interior of the pellet through the envelope layer surrounding the core.
The formation of the osmotic pressure in the interior of the pharmaceutical composition of the present invention occurs independently froi physiological influences such as pH, viscosity and periistalsis and depends solely on the enzyie activity; thl' release rate being finally controlled by the outel layer surrounding the pellet of the invention.
ii -i I 1; i; a r WO 89/00045 PCT/US88/02131 -6- Brief Description of the Drawing The invention will be better understood by reference to the drawing.
The drawing is an illustration of a pellet of the invention. The core of the pellet contains the active ingredient 1, the enzyme or enzyme mixture 2, the substrate 3 and, optionally, further granulation auxiliaries. The core is surrounded by the envelope layer 4.
Detailed Description of the Invention Suitable substrate polymers in accordance with the invention are substances whose enzymatic degradation leads to pharmacologically acceptable degradation products which are soluble in the gastro-intestinal juice. Exc&.ples are polyglucosides, glycogen, a-amylose, amylopectin, pullulan, laminarin, paramylum, callose, cellulose, inulin, phlean, mannans, xylans, arabinans, galactomannans, chitin, chitosan, gelatin, casein or ribonucleic acid. Suitable corresponding enzymes are a-amylase, amyloglucosidase, a-glucosidase, pullulanase, 0-glucosidase, cellulase, 0-fructosidase, mannasidase, pectinase, chitinase, proteases or ribonucleases. The combination of enzyme or enzyme mixture and substrates is chosen in such a way that the substrate is deg aded to water-soluble subunits. A preferred enzyme-substrate combination is a-amylase/pregelatinized corn starch or amylose.
The quantitative ratio of polymer to the corresponding enzyme depends on the desired duration of release and usually ranges from 100 1 and 100,000 1.
By a suitable selection of the quantitative ratio of polymer and corresponding enzyme, the duration of release of the pharmaceutical substance can be controlled to range from 8 to 24 hours. The core may additionally contain granulation auxiliaries, such as soluble dextrins, polyvinyl pyrrolidone or hydroxypropyl cellulose, which are known to the person skilled in the art.
WO 89/00045 PCT/US88/02131 -7- The envelope layer surrounding the core and retarding the release of the pharmaceutical substance comprises a film-forming macromolecular substance(s) which is essentially insoluble in the gastro-intestinal juices.
These are known to the expert. Ethyl cellulose with an ethoxy content of 47.5 to 49% is preferably used. Other suitable substances are hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, acrylic acid ester, methacrylic acid ester, shellac, cellulose acetate phthalate or copolymers of neutral methacrylic acid esters. The envelope layer additionally contains pore-forming substances which are likewise known to the expert. Polyethylene glycol with a molecular weight in the range from 200 to 6,000 is particularly preferred for this purpose. Other suitable pore formers are propylene glycol, diethylphthalate, dibutylphtalate, triacetin, citric acid ester, glycerin, sorbitol or ethylene glycol. The type and quantity of these additives depend on the rate at which the pharmaceutical substance is to be released.
Pharmaceutical substances for the pharmaceutical composition in accordance with the invention are for instance antibiotics, hormones, antipyretics, antidiabetics, coronary dilators, cardiac glycosides, spasmolytics, antihypertensive agents, psychotropic agents, agents for treating migraine, corticoids, analgesics, antirhumatics, anticholinergics, sympatholytics, sympathomimetics, vasodilators, anticoagulants, or antiarrhythmics.
The drawing shows the structure of a pellet of the invention. The core contains the active ingredient 1, the enzyme or enzyme mixture 2, the substrate 3, and optionally further granulation auxiliaries.
The core is surrounded by the envelope layer 4 comprising a water-insoluble polymer(s). The envelope layer 4 additionally contains ;~ce soluble pore-forming substances, the quantitative portion of which is from 5 to of weight of the envelope layer, and which result upon ingestion in pores 5 being formed in the envelope layer.
WO 89/00045 PCT/US88/02131 The pharmaceutical composition of the invention shows the following advantages: The pharmaceutical substance is released from the individual pellets irrespective of the mentioned physiological influences, the pH value, gastro-intestinal motility and viscosity.
2. Variations in the gastro-intestinal passage times are compensated for by the "multiple unit dosage form" principle. This way, the re'producibility of the release of the pharmaceutical substance is improved compared to Osmogit" preparation.
3. The substances resulting from the enzymatic degration of the polymers are physiologically acceptable; in addition, they are not released punctiformly as in the case of the Osmogit" preparations, but are released into the gastro-intestinal tract from the entire surface of the pharmaceutical 'composition. Thus a "cutting torch" effect is avoided.
4. By controlling the variation in the quantitative ratio of enzyme substrate, it is possible to control the liberation kinetics correspondingly, as the reaction rate constant of the degration of the polymer only depends on the enzyme concentration.
The following Examples provided to illustrate the invention, but they are not intended to limit the invention.
Example 1 A pharmaceutical compiosition is prepared as Sl follows: The corresponding amounts of polymer, pharmaceutical substance and enzyme are thoroughly mixed in a dry state. The mixture is then thoroughly moistened by a small amount of isopropanol. The mixture is granulated with a 5% aqueous solution of hydroxypropyl cellulose (average molecular weight 100,000).
WO 89/00045 PCT/US88/02131 -9- The moist granulate so prepared in extruded by means of a hole sieve, the holes having a diameter of 1 mm.
The extrudate is transferred into a suitable spheronizer and rendered round at maximum rotation. The crude pellets are transferred to a fluidized bed dryer and dried in the air stream. The dried pellets are sprayed in the fluidized bed dryer with a suspension of ethyl cellulose (7 weight polyethylene glycol (PEG) 6000 and talcum in ethanol.
After application of the whole envelope layer, the pellets are dried for 30 more minutes. Finally, the pellets are filled into hard gelatin capsules by means of a suitable capsulating machine. By this process a product having the following composition is prepared: ingredients pregelatinized starch 32.68 corn starch (native) 32.623 a-amylase 0.007 hydroxypropyl cellulose 1.63 crystal violet (model substance) 1.63 ethyl cellulose 19.70 PEG 6000 7.84 talcum 3.92 i WO 89/00045 PCT/US88/02131 Example 2 Example 1 was repeated except for using a higher amylase portion. The resulting product had the following composition: Ingredients pregeatinized starch 32.86 corn starch (native) 32.827 a-amylase 0.033 hydroxypropyl cellulose 1.15 crystal violet model substance) 1.64 ethyl cellulose 19.67 PEG 6000 7.88 talcum 3.94 Release of the Pharmaceutical Substance The amount of the pharmaceutical substance released in vitro was measured in the paddle apparatus of USP XXI, incorporated herein by reference. For this purpose, 100 mg each of the products prepared according to Examples 1 and 2 were incubated in 900 ml of water at 37 0
C.
The stitring rate was 50 rpm. The amounts of pharmaceutical substance released at the time of removing them were determined spectrophotometrically.
The results are shown in Table I. The increase in the enzyme concentration caused an increase in the release of the pharmaceutical substance per time unit.
WO 89/00045 PCT/US88/02131 -11- Table I Amount of released crystal violet Time (h) 0.75 1.25 3.75 4.75 5.75 6.75 23.0 Example 1 1.6 4.2 6.4 12.5 17.5 21.5 23.5 33.1 Ex a p1e 2 9 19.4 28.0 32.4 38.5 43.2 43.9 44.6 46.9 Example 3 A pharmaceutical composition containing theophyllin as a pharmaceutical substance was prepared in accordance with example 1. Its .composition is shown in Table II.
Comparative Example Another pharmaceutical composition was prepared in accordance with Example 3, however without adding an enzyme. The composition is also shown in Table II.
w-~ if WO 89/00045 PCT/US88/02131 -12- Table II Composition of the theophyllin-containing products.
Ingredients Example 3 Comparative Example pregelatinized starch corn starch (native) a-amylase hydroxypropyl cellulose theophyllin (model substance) ethyl celluose PEG 6000 talcum 26.16 26.16 0.026 1.16 5.81 25.42 10.17 5.09 26.17 26.17 1.16 5.81 25.43 10.17 5.09 Releas': of the Pharmaceutical Substance The release of the pharmaceutical suostance was also determined under the conditions stated in Examples 1 and 2. The results are shown in Table III.
Table III Amount of released theophyllin mg released Example 3 C Time (h) omparative Example 3.41 4.26 5.28 5.95 7.15 8.16 13.6 1.70 2.72 3.41 3.42 3.74 4.42 4.76
I
tl WO 89/00045 PCT/US88/02131 -13- Example 4 A pharmaceutical composition containing flunarizin as a pharmaceutical substance was prepared in accordance with Example 3. Its composition is shown in Table IV.
Table IV Composition of a flunarizin-containing product Ingredients pregelatinized starch 26.16 corn starch (native) 26.16 a-amylase 0.026 hydroxypropyl cellulc- 1.16 flunarizin (model substance) 5.81 ethyl cellulose 25.42 PEG 6000 10.17 talcum 5.09 Example A pharmaceutical composition containing salbutamol sulfate as a pharmaceutical substance was prepared in accordance with Example 4. Its composition is shown in Table V.
"NVO 89/00045 PCT/US88/02 131 Table V Composition of a salbutamol sulfate-containing product Ingredients% microcrystalline cellulose 35.5 corn starch 7 7 pregelatinized starch 10.65 hydroxypropyl cellulose 41 c-anylase 0.011 amyloglucosidase 0. 11.
0.51471 1:2:0.1 ethylacrylate/niethylmethac rylate/t rime thylami noethyl- 'methacrylate chloride copolymer 21.46 propylene glycol 2.13 I (highly dispersed silicic aicid) 1,086 Psalbutamol sulfate 6.88

Claims (7)

1. A pharmaceutical composition in pellet form comprising i core, which core contains the pharmaceutical substance, and an envelope layer surrounding the core, the composition being characterized in that a) the core contains the pharmaceutical substance or a mixture of pharmaceutical substances, a pharmacologically acceptable enzyme or enzyme mixture, a pharmacologically acceptable polymer as a filler and as a substrate for the enzyme or enzyme mixture, and b) the enI'elope layer contains a pharmacologically acceptable, water-insoluble, film-forming macromolecular substance and a water-soluble pore former.
2. q-e4pharmaceutical composition according to Claim 1, wherein the combination of enzyme or enzyme mixture and substrate is selected in such a way that the substrate is degraded to water-soluble subunits. A
3. phe pharmaceutical composition according to Claim 1, wherein the quantitative ratio of enzyme to substrate is selected in such a way that the duration of release of the pharmaceutical substance is from about 8 to 24 hours. A
4. e-pharmaZeutical composition according to Claim 1, wherein the substtrate is polyglucoside, glucogen, amylose, amylopectin, pullulan, laminarin, paramylon, callose, cellulose, inulin, phlean, mannan, xylane, arabinan, galactomannan, chitin, chitosan, gelatin, casein or ribonucleic acid or a combination thereof. WO 89/00045 PCT/US88/02 131 -16- 4.-,,pharmaceutical composition according to Claim 1, wherein the enzyme is cc-amylase, amyloglucosidase, c-glucosidase, pullulanase, p-glucosidase, celJlu3ase, 7fructosidase, mannosidase, pectinase, chitinase, protease, ribonuclease-1 or a combination thereof.
6. rpharmaceutical composition according to Claim 1, wherein the enzyme is c-amylase and a stibstrate is amylose.
7. -44e~pharmaceutic~al composition according to Claim 1, wherein the pharmaceutical substance is salbutamol or the sulfate salt thereof.
158. eIpharmaceutical composition according to Claim 1, wherein the composition is filled in hard gelatin capsules. -17- 9. A pharmaceutical composition as claimed in claim 1 substantially as hereinbefore described with reference to any one of the examples. 1 o o*o ee 1
AU21245/88A 1987-06-30 1988-06-23 Pellets with enzymatically controlled drug release Ceased AU618748B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE3721574 1987-06-30
DE19873721574 DE3721574A1 (en) 1987-06-30 1987-06-30 MEDICINAL PRODUCTS IN THE FORM OF PELLETS WITH ENZYMATICALLY CONTROLLED DRUG RELEASE
PCT/US1988/002131 WO1989000045A1 (en) 1987-06-30 1988-06-23 Pellets with enzymatically controlled drug release

Publications (2)

Publication Number Publication Date
AU2124588A AU2124588A (en) 1989-01-30
AU618748B2 true AU618748B2 (en) 1992-01-09

Family

ID=6330589

Family Applications (1)

Application Number Title Priority Date Filing Date
AU21245/88A Ceased AU618748B2 (en) 1987-06-30 1988-06-23 Pellets with enzymatically controlled drug release

Country Status (7)

Country Link
EP (1) EP0370049A1 (en)
JP (1) JPH02504145A (en)
AU (1) AU618748B2 (en)
DE (1) DE3721574A1 (en)
NZ (1) NZ225158A (en)
WO (1) WO1989000045A1 (en)
ZA (1) ZA884622B (en)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5049395A (en) * 1989-03-09 1991-09-17 Micro Vesicular Systems, Inc. Controlled release vehicle
SE8901279D0 (en) * 1989-04-10 1989-04-10 Pharmacia Ab COMPOSITION
DE3918801A1 (en) * 1989-06-06 1991-05-08 Schmidt Walter Multi-layered pharmaceutical particle with controlled release rate - has at least inner layer contg. active ingredient and outer layer contg. rate controlling component, e.g. polymer
US5252318A (en) * 1990-06-15 1993-10-12 Allergan, Inc. Reversible gelation compositions and methods of use
US5603956A (en) * 1990-11-27 1997-02-18 Labopharm Inc. Cross-linked enzymatically controlled drug release
NL9201195A (en) * 1992-07-03 1994-02-01 Tno PREPARATION FOR THE REGULATED DELIVERY OF AN ACTIVE SUBSTANCE AND METHOD FOR PREPARING SUCH A PREPARATION.
NL9201196A (en) * 1992-07-03 1994-02-01 Tno PREPARATION FOR THE REGULATED DELIVERY OF AN ACTIVE SUBSTANCE AND METHOD FOR PREPARING SUCH A PREPARATION.
HU221591B (en) * 1992-07-24 2002-11-28 Labopharm Inc. Gross-linked polyhydroxylic material for enzymatically controlled drug release
JPH08507700A (en) * 1992-12-28 1996-08-20 ボシュ アンド ロム インコーポレイテッド Composition for controlled release of active substance in aqueous medium
ES2288152T3 (en) * 1999-08-09 2008-01-01 Dainippon Sumitomo Pharma Co., Ltd. SOLID PREPARATIONS CONTAINING CHITOSANE POWDER AND ASSOCIATED PRODUCTION PROCEDURE.
AU1556000A (en) * 1999-11-22 2001-06-04 Akzo Nobel N.V. Composition allowing predefined and controlled release of active ingredient, preparation thereof and use
FR2938433B1 (en) * 2008-11-19 2011-09-09 Francois Fauran PHARMACEUTICAL COMPOSITIONS USING INULIN AS A GRANULATING EXCIPIENT
JP6069782B2 (en) * 2012-11-09 2017-02-01 国立大学法人佐賀大学 Substrate-responsive autonomous vibration microcapsules
CN113172887B (en) * 2021-03-15 2023-04-07 中国科学院上海硅酸盐研究所 Coaxial support material with slow release function

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3493652A (en) * 1962-09-14 1970-02-03 Charles W Hartman Controlled release medicament

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3977404A (en) * 1975-09-08 1976-08-31 Alza Corporation Osmotic device having microporous reservoir
US4261969A (en) * 1979-05-03 1981-04-14 World Health Organization Controlled drug release composition
DE2923279C2 (en) * 1979-06-08 1987-07-09 Kali-Chemie Pharma Gmbh, 3000 Hannover Process for the preparation of pancreatin pellets and pharmaceutical compositions containing them
JPS5640151A (en) * 1979-09-06 1981-04-16 Daiichi Seiyaku Co Coating device for tablet
WO1983003061A1 (en) * 1982-03-04 1983-09-15 Battelle Development Corp Dual microcapsules
US4609374A (en) * 1985-04-22 1986-09-02 Alza Corporation Osmotic device comprising means for governing initial time of agent release therefrom

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3493652A (en) * 1962-09-14 1970-02-03 Charles W Hartman Controlled release medicament

Also Published As

Publication number Publication date
DE3721574A1 (en) 1989-01-12
AU2124588A (en) 1989-01-30
JPH02504145A (en) 1990-11-29
NZ225158A (en) 1990-12-21
ZA884622B (en) 1990-02-28
WO1989000045A1 (en) 1989-01-12
EP0370049A1 (en) 1990-05-30

Similar Documents

Publication Publication Date Title
AU618748B2 (en) Pellets with enzymatically controlled drug release
JP3806740B2 (en) Drug delivery composition
US5422121A (en) Oral dosage unit form
US5294448A (en) Delayed release formulations
CA2337046C (en) Sustained release pharmaceutical preparation
CN100352432C (en) Nateglinide-containing preparation
US5540945A (en) Pharmaceutical preparations for oral administration that are adapted to release the drug at appropriate sites in the intestines
LV12399B (en) Improved pulsatile once-a-day delivery systems for minocycline
AU1518600A (en) Controlled release formulation for water soluble drugs
EP1311247A1 (en) Oral pharmaceutical dosage forms for pulsatile delivery of an antiarrhythmic agent
CN1195984A (en) Pharmaceutical formulations containing darifenacin
JPH09505609A (en) Controlled-release dosage form of azithromycin
HU227490B1 (en) Sustained release pharmaceutical preparation containing carvedilol
EP0616802B1 (en) Oral preparation for release in lower digestive tracts
US5776489A (en) Controlled release carbonic anhydrase inhibitor containing pharmaceutical compositions from spherical granules in capsule oral dosage unit form
EP0264989B1 (en) Galenic formulations for oral use of rhein derivatives with delayed release for therapeutical use
MXPA04007894A (en) Colonic release composition.
US4954349A (en) Oral magnesium and potassium compositions and use
JPS61221115A (en) Manufacture of tablet
GB2134785A (en) Slow-release compositions
AU619481B2 (en) Oral magnesium and potassium compositions and use
EP0540813B1 (en) Sustained release formulations of acetazolamide
CN1232386A (en) Colonic delivery of weak acid drugs
JP3456211B2 (en) Long-acting formulation
CN101006988A (en) Slow release preparation of puerarin