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WO1993005770A1 - Preparation a longue duree d'action - Google Patents

Preparation a longue duree d'action Download PDF

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Publication number
WO1993005770A1
WO1993005770A1 PCT/JP1992/001183 JP9201183W WO9305770A1 WO 1993005770 A1 WO1993005770 A1 WO 1993005770A1 JP 9201183 W JP9201183 W JP 9201183W WO 9305770 A1 WO9305770 A1 WO 9305770A1
Authority
WO
WIPO (PCT)
Prior art keywords
sustained
release
drug
outer layer
inner layer
Prior art date
Application number
PCT/JP1992/001183
Other languages
English (en)
Japanese (ja)
Inventor
Yoshio Ueda
Norio Ohnishi
Mitsuru Yasumura
Kazuto Okimoto
Kouji Kitada
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
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 Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Publication of WO1993005770A1 publication Critical patent/WO1993005770A1/fr

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • the present invention relates to a sustained-release tablet-type preparation having a multilayer structure of two or more layers. More specifically, the outer layer is provided as a sustained release to have a self-adhesive property with a time lag, and the inner layer is rapidly dissolved.
  • the present invention relates to a long-acting preparation that can continue to provide a therapeutically or prophylactically effective high in vivo concentration even after being eluted with a time lag.
  • DDS Drug Delivery System
  • Conventional long-acting drugs include, for example, water-insoluble or poorly soluble Or a so-called matrix tablet in which a drug is dispersed in a water-insoluble or poorly soluble cross-linked matrix, etc., and these are drugs in the film or matrix.
  • Various formulations have been designed based on the concept that release is controlled by the resistance when the drug is diffused. More specifically, the mode of drug release in these preparations is driven by the concentration gradient of the drug in the preparation caused by the permeation of water (diffusion-controlled). The elution rate is reduced due to relaxation of the diffusion and increase in the diffusion distance.
  • the above-mentioned other enteric-coated preparations include the above-mentioned other enteric-coated preparations, which release a substance gradually in the process of going from the stomach to the intestinal tract by utilizing the difference in solubility due to pH.
  • pH is susceptible to individual differences, age differences, stomach food volume, circadian fluctuations, mental state fluctuations, etc. The disadvantage is that it must be very uncertain.
  • the applicant has found that the drug release rate is close to constant (zero-order release), and is affected by fluctuations in pH conditions and changes in stirring intensity during drug disintegration tests.
  • a monocycline consisting of disintegrating granules and wax containing the active ingredient is used.
  • This preparation contains a tablet which is tableted after applying a box to the surface of a disintegrating granule containing the principal component.
  • the wax part gradually dissolves, and the granules on the surface of the tablet come into contact with body fluids and release the drug in sequence.However, by controlling the amount of disintegrant and the amount of wax mixed into the granules This has the advantage that the degree of sustained release can be controlled.
  • the controlled release of the drug has been controlled with higher precision.On the other hand, even if a part of the drug is released with a delay due to the controlled release, the release of the drug is controlled. If the site is in the gastrointestinal tract with low absorption efficiency, such as the lower small intestine, the problem arises that the absorption of the drug becomes insufficient and the effect of sustained release cannot be fully enjoyed. This problem is even more pronounced when the drug is a poorly soluble drug.
  • the present invention has been made in view of such circumstances.
  • the present invention controls the sustained release of a drug by giving a time difference to the release of the active ingredient, and suppresses the release of a delayed drug from the absorption in the lower small intestine.
  • the purpose is to provide tablets that can be sufficiently absorbed at the site even if released to a part with low yield rate, and can maintain and maintain the concentration in the body at the concentration required for treatment or prevention. is there.
  • the pharmaceutical preparation of the present invention which has achieved the above object, has a two-layer structure or a multi-layer structure capable of forming a multi-layer structure as required, and the inner layer contains the active ingredient.
  • the basic point is that the outer layer is constituted by a sustained-release part containing the same or similar main drug as the above-mentioned main drug.
  • Figure 1 shows the in vitro dissolution test results.
  • Figures 2 and 3 are graphs showing the results of various changes in the experimental conditions in the in vitro dissolution test.
  • FIG. 4 is a graph showing in vivo oral absorbability.
  • composition of the tablet of the present invention is a multi-layered type which can be composed of two layers or two or more layers as described above, but the most typical one is a two-layer type. Therefore, in the following description, the case of the two-layer type will be mainly described, that is, the case of an inner layer and an outer layer will be described. However, a coloring layer, a sugar coating layer, or a protective layer is provided further outside the outer layer, or Similarly, a fast-acting layer containing the active substance and having excellent fast solubility is provided further outside the outer layer, or an intermediate layer containing the active substance having a dissolution / release property at an intermediate level between the fast-dissolving portion and the sustained-release portion between the outer layer and the inner layer. Is not necessarily excluded.
  • each layer of the tablet of the present invention includes not only a case where all the compounds are the same compound, a case where the compound is another compound having the same drug, and a case where the compound is another compound having similar drug effect.
  • the case where the compounds have the same efficacy and the same compounds will be described as representative examples.
  • the same compound in the above description includes the case where the compound is an acid or a base and forms a salt with various bases or acids, and the base or acid for forming the salt is different. Have been Should be considered the same compound.
  • the basic composition of the pharmaceutical composition of the present invention lies in that the quick-dissolve portion containing the active substance is arranged on the center side of the tablet and the sustained-release section containing the active substance is arranged on the outer peripheral side of the tablet.
  • the drug-containing sustained-release part on the outer periphery first descends sequentially in the gastrointestinal tract while gradually disintegrating due to the body fluid, and after a considerable period of time, a part of the drug-containing fast-dissolving part becomes part of the body fluid.
  • the collapse of the rapid melting zone starts immediately from the contact area.
  • the time lapse after taking the drug is divided into the initial, middle, and late stages of taking the drug.
  • the main drug gradually released from the sustained-release part gradually disintegrates into the gastrointestinal tract. It is expected that it is gradually absorbed along the body and acts in a direction that maintains a humorous body fluid concentration.
  • the principal drug that is disintegrated and released from the fast-dissolving part of the tablet that has reached the middle or lower part of the small intestine for example Is expected to be rapidly absorbed from the gastrointestinal tract and to continue to maintain the body fluid concentration at a high level.
  • the main drug-containing quick-dissolving portion which is an inner layer component of the tablet of the present invention, is a portion expected to rapidly release the main drug into the body fluid when it comes into contact with the body fluid, and is a pharmaceutical preparation for rapidly dissolving the main drug.
  • a technology that has been conventionally employed.
  • a method of mixing and kneading the active ingredient with a disintegrant, excipients, and various additives generally used in the art to form granules, and then compressing the granules into an inner layer tablet is exemplified. Is done.
  • examples of the disintegrant include various starches (eg, corn starch, corn starch, rice starch, new paper).
  • Starch carboxymethyl starch, etc.
  • rubbers eg, gum arabic
  • cellulose derivatives eg, carboxymethylcellulose calcium, carboxymethylcellulose sodium, low-substituted hydroxypropylcellulose, bridge carboxymethylcellulose sodium
  • various ion-exchange resins for example, polyamide and polymethacrylate
  • excipient include lactose, sucrose, mannite and the like.
  • the disintegrants and excipients as exemplified above are appropriately selected in consideration of the properties of the main drug and the intended cycling time, etc., and if necessary, the use of two or more in combination is also permitted.
  • the main ingredient is insoluble or very poorly soluble in water and is considered to be insufficiently absorbed from the digestive tract, use a natural or synthetic water-soluble polymer in combination with the above granules. Is recommended.
  • These water-soluble polymer substances may be added together with the base drug, disintegrant, excipients, or the like, or may be added sequentially in any order and mixed and kneaded to form granules.
  • the active ingredient is dispersed in a water-soluble polymer in advance, dried and then led to an easily soluble dosage form such as a solid dispersion. In some cases, it may be advisable to produce granules by mixing and kneading them with an active polymer substance).
  • water-soluble polymer substance first, as a natural substance, for example, a cellulose derivative (for example, hydroxypizole pizoremethinoresenorelose, methinoresenolerose, hydroxypoxypyrucellulose, carboxymethylcellulose, etc.), or Polysaccharides (eg pullulan, dextran, etc.) Examples thereof include polyvinyl pyrrolidone, cross-linked polyvinyl pyrrolidone, polyethylene oxide and the like. In such a case, an appropriate selection is made according to the degree of poor solubility of the active ingredient, and two or more of them can be used in combination as needed.
  • a natural substance for example, a cellulose derivative (for example, hydroxypizole pizoremethinoresenorelose, methinoresenolerose, hydroxypoxypyrucellulose, carboxymethylcellulose, etc.), or Polysaccharides (eg pullulan, dextran, etc.)
  • a cellulose derivative for example, hydroxypizo
  • the amount of disintegrant that can be used during the production of the granules is not particularly limited, but may be appropriately determined in consideration of the type of the disintegrant, the properties of the active ingredient, and the intended quick-dissolving property. It is selected from the range of 10 to 75% by weight, preferably 40 to 60% by weight.
  • the amount of the water-soluble polymer compound used is not particularly limited, and may be appropriately determined in consideration of the degree of poor water solubility of the active ingredient, the type of the water-soluble polymer substance, and the like. It is selected from the range of 5 to 60% by weight, preferably 5 to 40% by weight.
  • the quick-dissolving granules thus formed are tableted with a lubricant such as magnesium stearate, calcium stearate, talc, corn starch, etc. according to a conventional method to form the fast-dissolving inner layer portion of the present invention. Is done.
  • a lubricant such as magnesium stearate, calcium stearate, talc, corn starch, etc.
  • the main drug-containing sustained release portion which is an outer layer component of the tablet of the present invention, is a portion expected to gradually release the main drug into the body fluid when it comes into contact with the body fluid.
  • the pharmaceutical composition for release general-purpose sustained release technology conventionally used can be used.
  • the granules prepared for the inner layer side as described above are subjected to a boxing process to prepare a box-coated outer layer side structure, which is coated on the outer periphery of the tableted quick-dissolving inner layer portion.
  • the present invention can be obtained by press-coating.
  • the wax used here is insoluble or difficult to dissolve in water
  • various waxes for example, carnauba wax and the like
  • various hardened oils for example, soybean hardened oil, castor hardened oil, and the like
  • paraffins, and the like may be used. These may be used alone, or may be used alone. The above may be used in combination.
  • the granules are added to the melt of the box described above, kneaded, dried and sized to obtain sustained-release granules.
  • the amount of the wax used is not particularly limited, and may be determined as appropriate depending on the properties of the wax and the main drug used, the intended cycling time, and the like. From 10 to 70% by weight, preferably from 20 to 60% by weight.
  • the granules prepared as the inner layer-side structure were subjected to a boxing process to produce an outer layer-side formed body.
  • the outer layer side structure produced by such a method has exactly the same granular structure as that of the inner layer side except for the wax treatment.
  • the present invention includes such a case in the technical scope, the present invention naturally includes that the granule composition on the inner layer side and that on the outer layer side are separately formulated in accordance with the respective properties. For example, in view of the requirement that the inner layer side be rapidly soluble in disintegrants, it may be recommended to mix more disintegrant than the outer layer side granules.
  • the amount of the water-soluble polymer can be reduced as necessary and possible as much as that of the granules on the outer layer side.
  • the water-soluble polymer material on the side be 15-40% by weight, preferably 25-35% by weight.
  • ethyl cellulose In performing the Peggs treatment, other components may be used in combination for the purpose of further finely controlling the sustained release property of the wax or for promoting the disintegration of the wax at a stable rate.
  • An example of such a third component is ethyl cellulose. Since the chemical properties (eg, water solubility and viscosity) of ethyl cellulose change depending on the degree of substitution of the ethyl group, it is recommended to select the one with the optimal degree of substitution according to the purpose of addition. . In general, it is desirable to select a material having a viscosity of ffl in the range of 7 to 1 cps using viscosity as an index.
  • the amount of the ethylcellulose is determined in consideration of the viscosity and the purpose of the mixing, or the type of the wax. Usually, the amount is 0.75 to 2.5 (weight ratio), preferably the amount of the wax used. It is selected from the range of 0.8 to 1.5 (weight ratio).
  • ethyl cellulose as shown in the Examples described later, a method in which wax treatment is performed in a state where granules containing the active substance (solid dispersion for outer layer) before wax processing and ethyl cellulose are sufficiently mixed.
  • ethyl cellulose and PEX are sufficiently mixed and melted to coat the active ingredient-containing granules, or the expected amount of wax and A method in which chill cellulose is divided into two and each of the above methods is combined is freely employed.
  • the outer layer granules thus formed are press-coated on the outer periphery of the inner layer tablet, the lyophilic preparation of the present invention can be obtained.
  • Principles suitable for producing the cymbiotic preparation of the present invention are those which are considered to be suitable for oral administration, or those which are expected to be oral preparations if the cymbiotic property is achieved. All drugs are targeted. Therefore, the present invention is widely applied to cardiovascular drugs, gastrointestinal drugs, respiratory drugs, central nervous system drugs, autonomic nervous system drugs, hormonal drugs, antibiotics, and various other chemotherapeutic drugs. Among them, the development of a sustained release drug is strongly desired from the viewpoint of preventing heart attack, which is considered to be common when waking up, for example, when the cardiovascular agent is used, and the application of the present invention is particularly significant.
  • a circulatory agent is not particularly limited, but a typical example thereof is a dihydropyridine compound represented by the following general formula.
  • R 1 may be substituted by halogen, nitro and trihalo (lower) alkyl.
  • a phenyl group R 2 is a lower alkyl group or a lower alkoxy (lower) alkyl group, and Ra is a shear group.
  • R 1 Preferable examples of R 1 include 2-chlorophenyl, 2,3-dichlorophenyl, 2-difluorophenyl, 3-nitrophenyl, trifluoromethylphenyl and the like. Can be
  • R 2 Preferable examples of R 2 include methyl, ethyl, propyl, 2-port poxicetyl and the like.
  • R 3 examples include methyl, 2-aminoethoxymethyl and the like.
  • R 4 examples include methyl and the like.
  • R 5 examples include methyl, Echiru, isopropyl, I Sobuchiru, 2- Puropokishechiru, 2- (N- methyl-N- Benjiruami Roh) Echiru the like.
  • dihydropyridine compound represented by the above general formula examples include, for example, difendipine, dicardipine, nimodipine, disordipine, nitrendipine, amlodipine, fuerodipine, nildipine or nilvadipine, and among them, Most preferred is zirno ⁇ 'dipine.
  • dihydropyridin compounds such as manidipine, benidipine, dalodipine, isradipine and the like can also be exemplified as the preferred active compounds of the present invention.
  • a prescription example and a production example of a sustained release drug containing nilvadipine as a main drug are shown.
  • HPMC 2910 40mg L-HPC 45mg Lactose 57mg Soybean hardened oil 150mg Magnesium stearate 0.6mg
  • nilvadipine 24g
  • HPMC 2910 72 g
  • the obtained dried product was pulverized and sized, magnesium stearate (L2g) was added and mixed, and the mixture was tableted with a tableting machine to produce an inner layer tablet.
  • Production Example 2 Production of solid dispersion particles for outer layer of formulas A and B
  • nilvadipine 48 g
  • ethanol 1320 ml
  • lactose 342 g
  • the obtained dried product was pulverized and sized to prepare a solid dispersion for the outer layer.
  • nilvadipine 48g
  • ethanol 1320ml
  • lactose 120 g
  • 4 4 (TC solution of diluvadipine was added thereto, and kneaded for 10 minutes.
  • the resulting dried product was pulverized and sized to produce a solid dispersion for the outer layer.
  • the outer layer granules obtained in Production Examples 5 to 7 were press-coated on the outer periphery of the inner layer tablets produced in Production Examples 1 to 3, and the bilayer ⁇ A, B, C ( The prescription was as shown in C above).
  • the two-layer tablet A consisting of Formulation A of the present invention and the comparative plain tablet were in vitro in vitro at 200 rpm and 900 ml (first wave: pH 1.2) according to the Japanese Pharmacopoeia 12th Edition, Method II (paddle method).
  • first wave pH 1.2
  • Method II paddle method
  • the results are as shown in Fig. 1, where the measured values (each plot) for each of the comparison ordinary cells (the seals) exceeded 100% at all times, and were released immediately in a short time.
  • the two-layer tablet A (marked with ⁇ ) of Honkiaki showed an elution rate that was almost proportional to the time elapsed until the 7th hour, indicating excellent sustained release.
  • Approximate body weight 6 male beagle dogs weighing 1 Okg, fasting the normal tablet from the day before the test, orally administering 2 mg x 3 tablets, and oral administration immediately after that, forcibly administering 30 ml water per mouth did.
  • the two-layer tablet A was fasted from the day before the experiment, and fed 100 g of dog chow 30 minutes before administration of the two-layer tablet A, and orally administered one tablet. After each administration, approximately 3 ml of blood was collected from the forearm vein at each passage of time, and parin (5000 units) was added to the local administration. When the concentration of nilvadipine in poultry plasma was measured by gas chromatography, the results shown in Fig. 4 were obtained. It can be seen that the bilayer tablet A of the present invention exhibits excellent sustained release properties and also maintains a high blood concentration for a considerably long time.
  • the integrative fissure of the present invention has the following structure and structure, and the soil in the layer is gradually evacuated and exhibits excellent long-term gunning properties, while the main drug in the inner layer is At the time of release, the active drug in the inner layer is released rapidly, so that a high level of blood concentration is continuously maintained, and the effective blood concentration in the treatment and prevention is reduced. It was extremely prolonged.

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

Abstract

L'invention se rapporte à une préparation à longue durée d'action, qui possède une efficacité de longue durée remarquablement excellente par absorption par voie orale et qui comprend une tablette double couche constituée par une couche interne composée d'une partie rapidement soluble contenant un agent principal et par une couche externe composée d'une partie à libération prolongée contenant un agent principal.
PCT/JP1992/001183 1991-09-20 1992-09-17 Preparation a longue duree d'action WO1993005770A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP27031691 1991-09-20
JP3/270316 1991-09-20

Publications (1)

Publication Number Publication Date
WO1993005770A1 true WO1993005770A1 (fr) 1993-04-01

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PCT/JP1992/001183 WO1993005770A1 (fr) 1991-09-20 1992-09-17 Preparation a longue duree d'action

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002097132A (ja) * 2000-09-22 2002-04-02 Otsuka Pharmaceut Co Ltd シロスタゾール有核錠
JP2002370968A (ja) * 2001-06-12 2002-12-24 Towa Yakuhin Kk 薬物含有徐放性顆粒およびそれを含む錠剤
WO2003080057A1 (fr) * 2002-03-27 2003-10-02 Bayer Aktiengesellschaft Comprime-noyau de taille reduite contenant de la nifedipine
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US7144585B1 (en) 1999-03-25 2006-12-05 Otsuka Pharmaceutical Co., Ltd. Cilostazol preparation
US7732467B2 (en) 2003-05-15 2010-06-08 Alzheimer's Institute Of America, Inc. Method for reducing amyloid deposition, amyloid neurotoxicity and microgliosis
US8236346B2 (en) 2007-10-05 2012-08-07 Alzheimer's Institute of America, Inc Method for reducing amyloid deposition, amyloid neurotoxicity, and microgliosis with (-)-nilvadipine enantiomer
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61172813A (ja) * 1985-01-28 1986-08-04 Japan Atom Energy Res Inst ポリ乳酸を担体とする徐放性複合体の製造方法
JPS62246512A (ja) * 1986-04-18 1987-10-27 Fujisawa Pharmaceut Co Ltd 反復作用製剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61172813A (ja) * 1985-01-28 1986-08-04 Japan Atom Energy Res Inst ポリ乳酸を担体とする徐放性複合体の製造方法
JPS62246512A (ja) * 1986-04-18 1987-10-27 Fujisawa Pharmaceut Co Ltd 反復作用製剤

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US7144585B1 (en) 1999-03-25 2006-12-05 Otsuka Pharmaceutical Co., Ltd. Cilostazol preparation
JP2002097132A (ja) * 2000-09-22 2002-04-02 Otsuka Pharmaceut Co Ltd シロスタゾール有核錠
JP2002370968A (ja) * 2001-06-12 2002-12-24 Towa Yakuhin Kk 薬物含有徐放性顆粒およびそれを含む錠剤
WO2003080057A1 (fr) * 2002-03-27 2003-10-02 Bayer Aktiengesellschaft Comprime-noyau de taille reduite contenant de la nifedipine
US7732467B2 (en) 2003-05-15 2010-06-08 Alzheimer's Institute Of America, Inc. Method for reducing amyloid deposition, amyloid neurotoxicity and microgliosis
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8236346B2 (en) 2007-10-05 2012-08-07 Alzheimer's Institute of America, Inc Method for reducing amyloid deposition, amyloid neurotoxicity, and microgliosis with (-)-nilvadipine enantiomer
US8236347B2 (en) 2007-10-05 2012-08-07 Alzheimer's Institute Of America, Inc. Pharmaceutical compositions for reducing amyloid deposition, amyloid neurotoxicity, and microgliosis

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