EP0370049A1 - Pellets with enzymatically controlled drug release - Google Patents

Pellets with enzymatically controlled drug release

Info

Publication number
EP0370049A1
EP0370049A1 EP88906543A EP88906543A EP0370049A1 EP 0370049 A1 EP0370049 A1 EP 0370049A1 EP 88906543 A EP88906543 A EP 88906543A EP 88906543 A EP88906543 A EP 88906543A EP 0370049 A1 EP0370049 A1 EP 0370049A1
Authority
EP
European Patent Office
Prior art keywords
enzyme
pharmaceutical
pharmaceutical composition
substrate
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.)
Withdrawn
Application number
EP88906543A
Other languages
German (de)
French (fr)
Inventor
Horst-Georg Zerbe
Jorn Ullrich Becker
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 EP0370049A1 publication Critical patent/EP0370049A1/en
Withdrawn legal-status Critical Current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

Definitions

  • the present invention relates to a pharmaceutical composition in pellet form with enzymatically controlled release of the pharmaceutical substance.
  • pharmaceutical substances are administered to patients as pharmaceutical compositions with so-called sustained release. After the patient has taken the pharmaceutical composition, the pharmaceutical 0 substance is released in the gastro-intestinal tract slowly over several hours. In 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 c; pharmaceutical substance prevents plasma level peaks and undesired side effects may result 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 Q compressing it into tablets.
  • Suitable carrier 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. Examples are gum arabic, cellulose derivatives, water-soluble polyacrylic acid derivatives, polyvinyl pyrrolidone, tragacanth or guar.
  • 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 Q depends on the quantitative ratio of the pharmaceutical substance and the polymer forming the matrix.
  • the tablets, pellets or granules containing the pharmaceutical substance are coated with a lacquer layer of a film-forming
  • film formers are known to the expert.
  • preferred film formers are ethyl cellulose, polyvinylacetate, anionic polymers of methacrylic acid and methacrylic acid esters, acrylic and methacrylic acid ester
  • 2o copolymers such as 1:1 methacrylic acid/methacrylate copolymers and 2rl 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, 5 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.
  • US Patent 3,916,899 for instance, describes a • j o preparation (Osmogit R ) 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 5 preparation has been administered to the patient, gastro-intestinal fluid diffuses into the compartment containing the osmotically active agent, whereby the solution of the pharmaceutical substance is pressed into the gastro-intestinal tract by a specific opening provided 0 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.
  • a further disadvantage of this preparation is 0 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 5 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.
  • 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 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.
  • the technical problem underlying the present invention is to provide a pharmaceutical composition in pellet form comprising a core, which core contains the pharmaceutical substance, 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 individual variations of the gastro-intestinal passage times.
  • the core contains the pharmaceutical substance OL a mixture of pharmaceutical substances, a pharmacologically acceptable enzyme or enzyme mixture and a pharmacologically acceptable polymer as a filler and substrate for the enzyme or enzyme mixture
  • the envelope layer contains a pharmacologically acceptable, water-insoluble, film-forming macromolecular substance and a water-soluble pore-former.
  • 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.
  • 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 results in a continuous flow of the solution of the pharmaceutical 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 from physiological influences such as pH, viscosity and peristalsis and depends solely on the enzyme activity; the release rate being finally controlled by the outer layer surrounding the pellet of the invention.
  • 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 0 cote is surrounded by the envelope layer 4.
  • Suitable substrate polymers in accordance with g the invention are substances whose enzymatic degradation leads to pharmacologically acceptable degradation products which are soluble in the gastro-intestinal juice .
  • Examples are polyglucosides, glycogen, ⁇ -amylose, amylopectin, pullulan, laminarin, paramylum, callose, cellulose, inulin, o phlean, mannans, xylans, arabinans, galactomannans, chitin, chi.tosan, gelatin, casein or ribonucleic acid.
  • Suitable corresponding enzymes are ⁇ -amylase, amyloglucosidase, ⁇ -glucosidase, pullulanase, ⁇ -glucosidase, cellulase, ⁇ -fructosidase, mannosidase, pectinase, chitinase, 5" proteases or ribonucleases.
  • the combination of enzyme or enzyme mixture and substrates is chosen in such a way that the substrate is degraded to water-soluble subunits.
  • a preferred enzyme-substrate combination is ⁇ -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 5 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.
  • 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.
  • 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.
  • compositions 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, antirheumatics, anticholinergics, sympatholytics, sympathomimetics, vasodilators, anticoagulants, or antiarrhyth ics.
  • 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 water-soluble pore-forming substances, the quantitative portion of which is from 5 to 50% of weight of the envelope layer, and which result upon ingestion in pores 5 being formed in the envelope layer.
  • 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, i.e., the pH value, gastro-intestinal motility and viscosity.
  • the substances resulting from the enzymatic degration 5 of the polymers are physiologically acceptable; in addition, they are not released punctiformly as in the case of the Osmogit R preparations, but are released into the gastro-intestinal tract from the entire surface of the pharmaceutical, composition. Thus a "cutting torch" effect o is avoided.
  • a pharmaceutical composition is prepared as 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 5 small amount of isopropanol. The mixture is granulated with a 5% aqueous solution of hydroxypropyl cellulose
  • 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.
  • Example 1 was repeated except for using a higher amylase t - portion.
  • the resulting product had the following composition:
  • the amount of the pharmaceutical substance released in vitro was measured in the paddle apparatus of USP XXI, incorporated herein by reference. For this 5 purpose, 100 mg each of the products prepared according to Examples 1 and 2 were incubated in 900 ml of water at 37°C. The stirring rate was 50 rpm. The amounts of pharmaceutical substance released at the time of removing them were determined spectrophotometrically. 0 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.
  • a pharmaceutical composition containing theophyllin as a pharmaceutical substance was prepared in accordance with example 1. Its composition is shown in Table II.
  • composition was prepared in accordance with Example 3, however without adding an enzyme.
  • the composition is also shown in Table II.
  • composition of the theophyllin-containing products is Composition of the theophyllin-containing products.
  • a pharmaceutical composition containing flunarizin as a pharmaceutical substance was prepared in accordance with Example 3. Its composition is shown in Table IV.
  • pregelatinized starch 26.16 corn starch (native) 26.16 ⁇ -amylase 0.026 hydroxypropyl cellulose 1.16 flunarizin (model substance) 5.81 ethyl cellulose 25.42
  • a pharmaceutical composition containing salbutamol sulfate as a pharmaceutical substance was prepared in accordance with Example 4. Its composition is shown in Table V. Table V
  • Aerosil R (highly dispersed silicic acid) 1.086- salbutamol sulfate 6.88

Abstract

Sont décrites des compositions pharmaceutiques sous forme de comprimés à libération régulée de manière enzymatique de la substance pharmaceutique, comprenant un noyau et un couche enveloppant ledit noyau. Le noyau contient la substance pharmaceutique, une enzyme et un substrat destiné à l'enzyme. La couche d'enveloppe contient une substance macromoléculaire formant une couche mince insoluble dans l'eau ainsi qu'un élément formant des pores solubles dans l'eau.Described are pharmaceutical compositions in the form of tablets with enzymatically controlled release of the drug substance, comprising a core and a layer surrounding said core. The nucleus contains the drug substance, an enzyme and a substrate for the enzyme. The shell layer contains a water insoluble thin film macromolecular substance as well as a water soluble pore forming element.

Description

PELLETS WITH ENZYMATICALLY CONTROLLED DRUG RELEASE
Field of the Invention
0 The present invention relates to a pharmaceutical composition in pellet form with enzymatically controlled release of the pharmaceutical substance.
Background of the Invention 5
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 0 substance is released in the gastro-intestinal tract slowly over several hours. In 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 c; pharmaceutical substance prevents plasma level peaks and undesired side effects may result 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 Q compressing it into tablets. Suitable carrier 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. Examples are gum arabic, cellulose derivatives, water-soluble polyacrylic acid derivatives, polyvinyl pyrrolidone, tragacanth or guar. t- 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 Q 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
•j_5 material that is insoluble in the gastric juice. The corresponding film formers are known to the expert. Examples of preferred film formers are ethyl cellulose, polyvinylacetate, anionic polymers of methacrylic acid and methacrylic acid esters, acrylic and methacrylic acid ester
2o copolymers, such as 1:1 methacrylic acid/methacrylate copolymers and 2rl 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, 5 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. 0 All foregoing systems suffer from the disadvantage that once the patient has taken the pharmaceutical composition, the release rate of the pharmaceutical substance is subject to greater or smaller variations depending on the viscosity of the 5 gastro-intestinal content, the peristalsis or the pH value. This may, for instance, have as a consequence that the necessary 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, c 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 •jo preparation (OsmogitR) 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 5 preparation has been administered to the patient, gastro-intestinal fluid diffuses into the compartment containing the osmotically active agent, whereby the solution of the pharmaceutical substance is pressed into the gastro-intestinal tract by a specific opening provided 0 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 the osmotically active agent is pressed through the opening, 5 which may cause quite some side effects such as perforations of the patient's intestinal wall, constitutes a considerable disadvantage of this preparation. This is known as the so-called "cutting torch" effect.
A further disadvantage of this preparation is 0 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 5 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. 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 substance, 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 individual variations of the gastro-intestinal passage times. The problem is solved in that a) the core contains the pharmaceutical substance OL a mixture of pharmaceutical substances, a pharmacologically acceptable enzyme or enzyme mixture and a pharmacologically acceptable polymer as a filler and substrate for the enzyme or enzyme mixture, and b) the envelope layer contains a pharmacologically acceptable, water-insoluble, film-forming macromolecular substance and a water-soluble pore-former. 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 results in a continuous flow of the solution of the pharmaceutical 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 from physiological influences such as pH, viscosity and peristalsis and depends solely on the enzyme activity; the release rate being finally controlled by the outer layer surrounding the pellet of the invention. Brief Description of the Drawing
The invention will be better understood by c- 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 0 cote is surrounded by the envelope layer 4.
Detailed Description of the Invention
Suitable substrate polymers in accordance with g the invention are substances whose enzymatic degradation leads to pharmacologically acceptable degradation products which are soluble in the gastro-intestinal juice . Examples are polyglucosides, glycogen, α-amylose, amylopectin, pullulan, laminarin, paramylum, callose, cellulose, inulin, o phlean, mannans, xylans, arabinans, galactomannans, chitin, chi.tosan, gelatin, casein or ribonucleic acid. Suitable corresponding enzymes are α-amylase, amyloglucosidase, α-glucosidase, pullulanase, β-glucosidase, cellulase, β-fructosidase, mannosidase, pectinase, chitinase, 5" proteases or ribonucleases. The combination of enzyme or enzyme mixture and substrates is chosen in such a way that the substrate is degraded to water-soluble subunits. A preferred enzyme-substrate combination is α-amylase/pregelatinized corn starch or amylose. *0 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 5 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. 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, antirheumatics, anticholinergics, sympatholytics, sympathomimetics, vasodilators, anticoagulants, or antiarrhyth ics. 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 water-soluble pore-forming substances, the quantitative portion of which is from 5 to 50% of weight of the envelope layer, and which result upon ingestion in pores 5 being formed in the envelope layer. The pharmaceutical composition of the invention shows the following advantages:
1. The pharmaceutical substance is released from the individual pellets irrespective of the mentioned physiological influences, i.e., the pH value, gastro-intestinal motility and viscosity.
2. Variations in the gastro-intestinal passage times are 0 compensated for by the "multiple unit dosage form" principle. This way, the reproducibility of the release of the pharmaceutical substance is improved compared to OsmogitR preparation.
3. The substances resulting from the enzymatic degration 5 of the polymers are physiologically acceptable; in addition, they are not released punctiformly as in the case of the OsmogitR preparations, but are released into the gastro-intestinal tract from the entire surface of the pharmaceutical, composition. Thus a "cutting torch" effect o 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 5 the enzyme concentration.
The following Examples provided to illustrate the invention, but they are not intended to limit the invention.
Example 1 0
A pharmaceutical composition is prepared as 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 5 small amount of isopropanol. The mixture is granulated with a 5% aqueous solution of hydroxypropyl cellulose
(average molecular weight 100,000). 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 α-amylase 0.007 hydroxypropyl cellulose 1.63 crystal violet
(model substance) 1.63 ethyl cellulose 19.70
PEG 6000 7.84 talcum 3.92
Example 2
Example 1 was repeated except for using a higher amylase t- portion. The resulting product had the following composition:
Ingredients
0 pregelatinized starch corn starch (native) α-amylase hydroxypropyl cellulose crystal violet 5 (model substance) ethyl cellulose
PEG 6000 talcum
0 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 5 purpose, 100 mg each of the products prepared according to Examples 1 and 2 were incubated in 900 ml of water at 37°C. The stirring rate was 50 rpm. The amounts of pharmaceutical substance released at the time of removing them were determined spectrophotometrically. 0 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.
5 Table I
Amount of released crystal violet
Time (h)
0.75
1.25
2.0
2.5
3.75
4.75
5.75
6.75
23.0
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.
Table II
Composition of the theophyllin-containing products.
Ingredients Example 3 Comparative
Example
26.17 26.17
1.16
5.81 25.43 10.17 5.09
20 Release of the Pharmaceutical Substance The release of the pharmaceutical substance was also determined under the conditions stated in Examples 1 and 2. The results are shown in Table III.
25 Table III
Amount of released theophyllin
mg released
30
35
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 α-amylase 0.026 hydroxypropyl cellulose 1.16 flunarizin (model substance) 5.81 ethyl cellulose 25.42
PEG 6000 10.17 talcum 5.09
Example 5
A pharmaceutical composition containing salbutamol sulfate as a pharmaceutical substance was prepared in accordance with Example 4. Its composition is shown in Table V. Table V
Composition of a salbutamol sulfate-containing product
Ingredients _%
microcrystalline cellulose 35.5 corn starch 17.75 pregelatinized starch 10.65 hydroxypropyl cellulose 4.15 α-amylase 0.011 amyloglucosidase 0.11 talcum 0.5147
1:2:0.1 ethylacrylate/methyl- methacrylate/trimethylaminoethyl- methacrylate chloride copolymer 21.46 propylene glycol 2.13
AerosilR (highly dispersed silicic acid) 1.086- salbutamol sulfate 6.88

Claims

The claimed invention is:
1. 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 a) the core contains the pharmaceutical substance or 0 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 ς b) the envelope layer contains a pharmacologically acceptable, water-insoluble, film-forming macromolecular substance and a water-soluble pore former.
2. The pharmaceutical 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.
3. The 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.
4. The pharmaceutical composition according to
Claim 1., wherein the substrate 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.
5. The pharmaceutical composition according to Claim 1, wherein the enzyme is α-amylase, amyloglucosidaεe, -glucosidase, pullulanase, β-glucosidase, cellulase, β-fructosidase, mannosidase, pectinase, chitinase, protease, ribonucleases or a combination thereof.
6. The pharmaceutical composition according to Claim 1, wherein the enzyme is α-amylase and a substrate is a ylose.
7. The pharmaceutical composition according to Claim 1, wherein the pharmaceutical substance is salbutamol or the sulfate salt thereof.
8. The pharmaceutical composition according to Claim 1, wherein the composition is filled in hard gelatin capsules.
EP88906543A 1987-06-30 1988-06-23 Pellets with enzymatically controlled drug release Withdrawn EP0370049A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19873721574 DE3721574A1 (en) 1987-06-30 1987-06-30 MEDICINAL PRODUCTS IN THE FORM OF PELLETS WITH ENZYMATICALLY CONTROLLED DRUG RELEASE
DE3721574 1987-06-30

Publications (1)

Publication Number Publication Date
EP0370049A1 true EP0370049A1 (en) 1990-05-30

Family

ID=6330589

Family Applications (1)

Application Number Title Priority Date Filing Date
EP88906543A Withdrawn EP0370049A1 (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
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.
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.
EP0651634B1 (en) * 1992-07-24 1996-05-08 Labopharm Inc. Cross-linked polyhydroxylic material for enzymatically controlled drug release
SG47841A1 (en) * 1992-12-28 1998-04-17 Bausch & Lomb Controlled release composition for active substances into an aqueous medium
CA2378265C (en) 1999-08-09 2007-11-20 Dainippon Pharmaceutical Co., Ltd. Solid preparations containing chitosan powder and process for producing the same
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

Family Cites Families (7)

* 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
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
DE2923279B1 (en) * 1979-06-08 1980-11-20 Kali Chemie Pharma Gmbh Process for the production of pancreatin pellets
JPS5640151A (en) * 1979-09-06 1981-04-16 Daiichi Seiyaku Co Coating device for tablet
EP0102391A1 (en) * 1982-03-04 1984-03-14 Battelle Development Corporation Dual microcapsules
US4609374A (en) * 1985-04-22 1986-09-02 Alza Corporation Osmotic device comprising means for governing initial time of agent release therefrom

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8900045A1 *

Also Published As

Publication number Publication date
ZA884622B (en) 1990-02-28
AU2124588A (en) 1989-01-30
NZ225158A (en) 1990-12-21
AU618748B2 (en) 1992-01-09
JPH02504145A (en) 1990-11-29
DE3721574A1 (en) 1989-01-12
WO1989000045A1 (en) 1989-01-12

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