WO2003015824A1 - Sustained-release medicinal compositions - Google Patents

Sustained-release medicinal compositions Download PDF

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Publication number
WO2003015824A1
WO2003015824A1 PCT/JP2002/008011 JP0208011W WO03015824A1 WO 2003015824 A1 WO2003015824 A1 WO 2003015824A1 JP 0208011 W JP0208011 W JP 0208011W WO 03015824 A1 WO03015824 A1 WO 03015824A1
Authority
WO
WIPO (PCT)
Prior art keywords
water
drug
soluble
cyclodextrin
hydrophobic polymer
Prior art date
Application number
PCT/JP2002/008011
Other languages
French (fr)
Japanese (ja)
Inventor
Kaneto Uekama
Fumitoshi Hirayama
Yoichi Ikeda
Soko Motoune
Original Assignee
Wakunaga 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
Priority to JP2001-242234 priority Critical
Priority to JP2001242234A priority patent/JP2005022975A/en
Application filed by Wakunaga Pharmaceutical Co., Ltd. filed Critical Wakunaga Pharmaceutical Co., Ltd.
Publication of WO2003015824A1 publication Critical patent/WO2003015824A1/en

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Classifications

    • BPERFORMING OPERATIONS; TRANSPORTING
    • B82NANOTECHNOLOGY
    • B82YSPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Abstract

Medicinal compositions containing a complex of water-soluble drug with water-soluble cyclodextrin and a hydrophobic polymer. In such a composition, the water-soluble drug can be maintained in a stable state and the elution of the drug from the composition can be accurately controlled. Thus, preparations with the use of these medicinal compositions are useful as sustained-release preparations wherein the elution of the drug can be regulated and the drug effect can be exerted over a long period of time. In addition, the hydrophobic polymer can be blended and tabletted without granulation, which makes it possible to conveniently and safely produce sustained-release preparations.

Description

Bright fine manual release pharmaceutical composition art

The present invention relates to a pharmaceutical composition capable of controlled release of water soluble drugs. BACKGROUND

Sustained release formulations, the potency duration of drug, reduce side effects, a formulation was developed designed for the reduction of administration frequency reduction, the total dose of short drug of biological half-life. Controlled release of the drug in such sustained release formulations generally after dissolving the sustained-release base in an organic solvent or the like, a method of coating the drug surface, distributed or dissolved drug in controlled-release material base dissolved method of a method of adsorbing the drug to the ion exchange material, covering the drug with a semipermeable membrane material, is carried out by a method utilizing the osmotic pressure.

Among them, the controlled release of water soluble drugs, generally and this for a drug coating a hydrophobic base (the capsule method) or drugs that are dispersed in hydrophobic base diffusion process of Thus drug (matrix method) It has been performed by controlling. In particular the matrix method, the type of hydrophobic polymer, by adjusting the composition and amount, by incorporating a water-soluble polymer and release-modifying agent, if necessary, can be easily controlled releasing (elution) rate of the drug high usefulness from Rukoto, so far, the fats and oils and sustained-release base, which formulation blended mercaptopurine prills to (Int. J. Pharm. 41. 263 (1988)) and E chill cellulose and sustained-release base, this formulation blended with disopyramide phosphate (JP-a-8-133975) and the like have been reported.

Recently, the present inventors have found that hydroxypropyl hydrophobic base materials by kneading a hydrophobic Toripuchiru / 3-cyclodextrin and water soluble drugs - beta - By blending cyclodextrin emissions, water-soluble drug found to be able to control the elution (J. control. Rel., 66> 271-280 (2000)).

However, the sustained release formulations have been found so far, due to the long drug release time in the gastrointestinal tract, various physiological conditions of the gastrointestinal tract, for example, the amount of digestive fluid, PH, digestive enzyme, digestive tract movement influenced by the speed or the like, not necessarily that can be precisely control the release rate of the drug. Further, Toripuchiru i3- in the sustained release preparation using a cyclodextrin, prepared must be kneaded and dispersed using an organic solvent such as alcohol at, there are problems such that tableting is difficult, manufacturing and handling have been desired for the development of easy a sustained-release formulation.

The invention is capable of precisely controlled release of water-soluble drugs, and to provide a easily and pharmaceutical compositions that can be formulated. Disclosure of the Invention

The present inventors, in view of such circumstances, sustained-release base Ya slow release modifiers intensive research as a result for, the water-soluble drug and a water-soluble cyclodextrin inclusion or the deposited complexes, hydrophobic this pharmaceutical compositions comprising dispersed 'mixed sex polymer has an ability to control output release precise drug, and easily found can be formulated, Itaru seven this completed the present invention.

That is, the present invention is to provide a pharmaceutical composition comprising the complex and a hydrophobic polymer water-soluble drug and a water soluble cyclodextrin. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a graph showing the drug release rate of the pharmaceutical compositions and comparative formulations of the present invention.

2, in the pharmaceutical composition of the present invention, is a graph showing the effect of the drug release rate of different ingredient content. BEST MODE FOR CARRYING OUT THE INVENTION

Pharmaceutical compositions containing the complex and a hydrophobic polymer water-soluble drug and a water soluble cyclodextrin of the present invention, the inclusion or the deposited complex water-soluble drug in a water-soluble cyclodextrin, which hydrophobic are those formed by dispersing 'is mixed into the polymer, the water-soluble drug can be stably held, it is possible to control the release of the drug. It is described components of the present invention the pharmaceutical composition below.

Hydrophobic polymer of the present invention will become matrix to control the release of the drug is also of a, is insoluble in water, but are not particularly limited as long as it can be used as a medicine, molecular weight 1 0 is what is preferably 0 0 0 or more polymers. Specifically, for example, cellulose derivatives, copolymers of methacrylic acid mono-, and the like aminoalkyl methacrylate rates copolymers. - Here, as the cellulose derivatives, E chill cellulose, cellulose acetate, hydroxycarboxylic methyl cellulose phthalate and the like, particularly an average molecular weight

1 0 0 0 0-1 0 0 0 0 0 0 E chill cellulose are preferred.

The methacrylic acid copolymer, methacrylic acid-acrylic acid Echiru copolymer, methacrylic acid-methyl methacrylate copolymer and the like, and the Aminoarukiru methacrylates one copolymer, Echiru-methyl methacrylate-methacrylic acid chloride trimethyl acrylate ammonium Niu Mue chill copolymer. Among Akuriru acid Echiru-methyl methacrylate-methacrylic acid chloride Torimechiruan Moniumuechiru copolymer are particularly preferred.

Water-soluble drug of the present invention are formulated as complex as inclusion or attached to a water soluble cyclodextrin. This allows efficient control of the dissolution of water-soluble drug in a matrix of hydrophobic polymer.

Here, in the hydrophobic cavity of Shikurodeki string of 6-8 amino glucose is to form a cyclic structure and inclusion means a state in which drug molecules are 1-2 entered in the drug molecule and with adhesive There refers to a state in which chemically or physically binds to the extra-cavity portion of the cyclodextrin molecular units or crystal units.

The water-soluble cyclodextrin present invention, or soluble natural Shikurodekisuto phosphorus in water, a side chain for improving the hydroxyl group to a water-soluble of the cyclodextrin, For example hydroxyalkyl group, Darukoshiru group, a maltosyl group 1 or more introduced so-called cyclodextrin derivatives. Such water-soluble Shikurodekisuto phosphorus has a work to suppress the intrusion of water into the gel-like and becomes the matrix in the elution process the drug, the solubility of such a point of view with respect to water is very high cyclodextrin derivative conductors are preferred. Note that the cyclodextrin, refers to non-reducing maltooligosaccharides which continues to the annular one 1, 4 one Darukoshido bond shed glucose molecules 6 to 1 2, is produced from starch, glucose 6 eight one , beta-, § first mold mainly present Suruga, i3 type is preferred.

The water-soluble cyclodextrin present invention, hydroxy E chill cyclo dextrin Specifically, hydroxyalkylidene sharp cyclodextrin such as hydroxypropyl cyclodextrin, monomethyl cyclodextrin, dimethyl cyclo dextrin, trimethylcycloheptyl de Kiss Bok phosphorus, Surufobuchirue one Terushikurode

It can be mentioned, of which hydroxy E chill one over cyclodextrin, hydroxypropyl - beta-cyclodextrin, Darukoshiru - beta - cyclodextrin, Ma Rutoshiru 3- cyclodextrin are preferred, especially solubility 1 0 0 g / 1 0 O mL or more in a hydroxy E chill -i3- cyclodextrin and hydroxy Shipuropiru one β- cyclodextrin is preferred.

Examples of the water-soluble drug in the present invention, the type is rather limited in particular, a drug that dissolves in water 3 O mgZmL or more. The may contain two or more drugs simultaneously. As to such a drug, for example, sustained-release effect is analgesic required, antipyretics, antiarrhythmics, antihypertensives, antibiotics, bronchodilators, anti-tumor agents, 鎮晐 agents, diuretics and the like, specifically thereof include, for example, hydrochloric O Le, metoprolol tartrate, hydrochloride base Takisoro Ichiru, kanamycin sulfate, hydrochloric phenethyl conazole, flomoxef sodium, cefmetazole sodium, tartrate key evening Samaishin, Migurenin, sulpyrine, hydrochloric aprindine, hydrochloride pro force In'ami de, hydrochloride methoxy off enamine, choline theophylline, vincristine sulfate, Rani Musuchin, Kuen acid Okiserajin, and the like hydrochloric pirbuterol is. Incidentally, Xu Hoka effect is effective as the drug is highly soluble in water.

Compounding ratio of the drug and a water-soluble consequent opening dextrin in water-soluble drug and a water soluble cyclodextrin complexes varies depending on the type of drug, the water-soluble cyclodextrin to 7K soluble drug 1 0.1 to 1 of it is preferable to blend in a ratio, by increasing the ratio of water-soluble cyclodextrin, can reduce the dissolution rate.

Preparation of such water-soluble drug and a water-soluble cyclodextrin complexes, process for the preparation of known inclusion compounds, for example kneading method, solution method, as possible out be carried out using freeze-dry method. For example, according to the kneading method, a water-soluble drug and a water soluble cyclodextrin and mixed at the mixing ratio of the above, this water, ethanol or hydrous ethanol was added, a paste can be obtained by drying.

The content of each component of the present invention the pharmaceutical composition comprises a drug to be administered, drug solubility, the release rate of the drug which requires, wettability, clathrate forming ability, the mixing properties of the hydrophobic polymer It is determined by many factors, with respect to water-soluble drugs 1-5 0 parts by weight, although the combination of water-soluble cyclo dextrin 1-3 0 parts by weight and hydrophobic polymer 4 0-9 0 parts by weight preferably, to water-soluble drugs 5-3 0 parts by weight, the combination of water-soluble cyclodextrin 5-2 0 parts by weight and hydrophobic polymer 6 0-9 0 parts by weight it is particularly preferred. The compositions of the present invention in a conventional manner, uncoated tablets, coated tablets, dragees, enteric tablets, other troches, oral solid preparation for sublingual tablets, etc., be an ointment, a topical formulation of suppositories can.

For example, when producing tablets, and the complex of water-soluble drug and a water-soluble Shikurodekisuto phosphorus described above, it was mixed with a hydrophobic polymer, tumbling fluidized granulation method optionally dry granulation after granulation at may be a tablet. Incidentally, since the use of a hydrophobic polymer capable of forming a matrix by coupling between particles and the matrix base material in the present invention, it is tableted directly without granulation using an organic solvent can efficiently tablets of sustained-release can be manufactured.

The said formulations, commonly excipients used in the pharmaceutical preparations, binders, stabilizers, lubricants, preservatives, dyes, can be allowed to contain additives such as perfumes, Fi Lum further formulation It can also be coated, such as sugar-coated or enteric film.

The amount of the pharmaceutical composition of the present invention, administration subject, although varies depending upon symptoms or the like, for oral administration, as a dose of about 5 0~1 0 0 0 mg 1 time in normal adults, favored properly about 1 is a 0 0~3 0 O mg. In parenteral administration, the single dose varies depending on subject to be administered, target organ, symptoms, and administration method and the like, from about 1 0 0 0-3 0 1 once in normal adult in the form of suppositories is 0 O mg about. Example

Hereinafter, a more detailed explanation of the present invention through examples, the present invention is not limited thereto.

Example 1

Metoprolol tartrate 6 O mg and hydroxypropyl - 3- Shikurodekisuto phosphate 2 O mg a suitable amount of purified water was added to the peptidyl one strike-like, kneading about 3 0 minutes. Put kneaded product in a vacuum drier, dried completely at room temperature, the powder is pulverized. This composite powder was added to E chill cellulose 1 2 O mg, it was mixed for about 2 0 minutes, and formed into tablets with a diameter of 1 0 mm. The tablets, using the first 3 Japanese Pharmacopoeia disintegration test method No. 2 solution, subjected to dissolution test in dissolution test second method (paddle method) was measured over time tartrate Metopu opening roll elution volume. The results are shown in FIGS. Dissolution rate on the vertical axis indicates (%), indicating the time in minutes on the horizontal axis. Comparative Example 1

An appropriate amount of purified water was added to metoprolol tartrate 6 Omg lactose 1 Omg, to Bae one strike-like, kneading about 3 0 minutes. Put kneaded material in a vacuum dryer, a powder completely dry, pulverized at room temperature. These only by tableting in the same manner as in Example 1, subjected to dissolution test was measured over time tartrate Metopuro opening one Le elution volume. It is shown together with the results in Figure 1.

Comparative Example 2

Metoprolol tartrate 6 Omg hydroxypropyl one i3- cyclodextrin down 14 Omg prepared like in Comparative Example 1, subjected to dissolution test was measured over time tartrate meth pro port one Le elution volume. It is shown together with the results in Figure 1.

Comparative Example 3

Only metoprolol tartrate 6 Omg and E chill cellulose 14 Omg were mixed in the same manner as in Example 1 was tableted, subjected to the dissolution test was measured over time metoprolol tartrate elution volume. It is shown together with the results in Figure 1.

Example 2

Obtaining a composite powder in the same manner as in Example 1 using 3-Shikurodekisuto phosphorus 1 0 mg | - metoprolol tartrate 6 Omg and hydroxypropyl. This composite powder was added to E chill cellulose 1 3 Omg, after mixing for about 20 minutes, and formed into tablets with a diameter of 1 Omm. The tablets, using the first 3 Japanese Pharmacopoeia disintegration test method No. 2 solution, subjected to dissolution test in dissolution test second method (paddle method) was measured over time metoprolol tartrate dissolved volume. The results are shown in Figure 2. Dissolution rate on the vertical axis indicates (%), indicating the time in minutes on the horizontal axis.

Example 3

Obtaining a composite powder in the same manner as in Example 1 using metoprolol tartrate 6 Omg and hydroxypropyl one i3- Shikurodekisuto phosphorus 3 Omg. This composite powder was added to E chill cellulose 1 1 Omg, papermaking tablets in the same manner as in Example 1, a dissolution test row ivy. It is shown together with the results in Fig.

Example 4

Obtaining a composite powder in the same manner as in Example 1 using metoprolol tartrate 6 O mg and hydroxypropyl one / 3 Shikurodekisuto phosphoric 4 O mg. This composite powder was added to E chill cellulose 1 0 O mg, papermaking tablets in the same manner as in Example 1, a dissolution test row ivy. It is shown together with the results in Fig.

As a result, as shown in FIG. 1, a hydrin Rokishipuropiru I) 3-cyclodextrin was added to metoprolol tartrate is a water-soluble drug, clathrate, or a mixture powder with E chill cellulose, a hydrophobic ¾ polymer mixture and, tabletting the formulations is higher sustained release effect as compared with the comparative example were observed.

Further, as shown in FIG. 2, by appropriately adjusting the water-soluble cyclodextrin and a hydrophobic polymer, sustained release rate was found to be adjustable. Industrial Applicability

The pharmaceutical compositions of the present invention can be stably hold the water-soluble drug in the composition, also can be precisely controlled drug dissolution from the composition. Therefore, formulations using a pharmaceutical composition of the present invention elution of the drug can be suppressed, it is useful as a sustained release formulation capable of exhibiting the effects of long-term drug. Further using an organic solvent a hydrophobic polymer can be mixed, tableting without granulation, it is possible to produce a sustained-release preparation easily and safely.

Claims

The scope of the claims
1. Water-soluble drug and a water-soluble cyclodextrin complexes and pharmaceutical compositions containing a hydrophobic polymer. The pharmaceutical composition is according to claim 1, wherein.
3. Hydrophobic polymer is a cellulose derivative, aminoalkyl main evening chestnut rate copolyether mer and in the claims 1 or 2 pharmaceutical composition according those selected from methacrylic acid copolymers.
. To water-soluble drugs 1-5 0 parts by weight, any one of claims 1 to 3 containing a water-soluble consequent opening dextrin 1-3 0 by weight portion and a hydrophobic polymer 4 0-9 0 parts by weight the pharmaceutical composition according.
. 5 claims a pharmaceutical composition is a sustained release tablet:! The pharmaceutical group composition as set forth in any one 1-4.
PCT/JP2002/008011 2001-08-09 2002-08-06 Sustained-release medicinal compositions WO2003015824A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2001-242234 2001-08-09
JP2001242234A JP2005022975A (en) 2001-08-09 2001-08-09 Sustained release medicinal composition

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WO2003015824A1 true WO2003015824A1 (en) 2003-02-27

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WO (1) WO2003015824A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007177149A (en) * 2005-12-28 2007-07-12 Shield Lab:Kk Inclusion compound of thioctic acid or dihydrolipoic acid with branched cyclodextrin
JP6207291B2 (en) * 2013-08-07 2017-10-04 大同化成工業株式会社 The external preparation for composition

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58172311A (en) * 1982-04-02 1983-10-11 Kodama Kk Prolonged pharmaceutical preparation and its preparation
JPH04275235A (en) * 1991-03-01 1992-09-30 Hisamitsu Pharmaceut Co Inc Absorption-promoting agent and external preparation containing the same
US5399362A (en) * 1994-04-25 1995-03-21 Edward Mendell Co., Inc. Once-a-day metoprolol oral dosage form

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58172311A (en) * 1982-04-02 1983-10-11 Kodama Kk Prolonged pharmaceutical preparation and its preparation
JPH04275235A (en) * 1991-03-01 1992-09-30 Hisamitsu Pharmaceut Co Inc Absorption-promoting agent and external preparation containing the same
US5399362A (en) * 1994-04-25 1995-03-21 Edward Mendell Co., Inc. Once-a-day metoprolol oral dosage form

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
UEKAMA K. ET AL.: "Design and in vitro evaluation of slow-release dosage form of piretanide: utility of beta-cyclodextrin: cellulose derivative combination as a modified-release drug carrier", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 79, no. 3, 1990, pages 244 - 248, XP000101623 *

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