JPH0457645B2 - - Google Patents

Description

[Detailed description of the invention]

B. Industrial Application Field The present invention relates to an oral film-like sustained release preparation.
More specifically, after oral administration, the oral film-like drug is suspended in the stomach and gradually releases the drug, thus providing the drug at a concentration sufficient to obtain a therapeutic effect over a long period of time. Concerning release formulations. B. Prior Art Conventionally, various proposals have been made regarding formulations and formulation methods for delaying the release of drugs from formulations and sustaining the efficacy of drugs for a long period of time. Among these, the following examples are examples of attempts to maintain an effective blood concentration by releasing the drug over a long period of time while the drug remains in the stomach. Specifically, Japanese Patent Application Laid-open No. 49-61323 proposes that a core made of a drug be coated with a polymer film that swells in gastric fluid, and that its mechanical size prevents passage through the pylorus and prolongs the residence time in the stomach. JP-A-51-115910 discloses a method in which a large amount of a fatty substance with a light specific gravity is suspended in gastric fluid, and the drug is released through the formed hydrogel membrane. Are listed. JP-A No. 50-121418 describes a method in which hollow materials such as expanded polystyrene, hard gelatin capsules, and expanded grains are coated with a gastric fluid-resistant film, and then a drug is further coated so that the drug floats and remains in the gastric fluid. The method is described. JP-A-52-76418 discloses that a blowing agent mainly composed of bicarbonate is coated with a coating agent containing a drug, or a mixture of a blowing agent and a drug is coated with a conventional coating agent. , a method has been described in which the drug is suspended in gastric juice and is gradually released. Both methods have drawbacks such as insufficient sustained release effect of these drugs. C. Purpose of the Invention The present inventors, unlike these prior art,
We are conducting intensive research into drug compositions to treat local gastric diseases and systemic diseases for which sustained drug release is expected to be more effective by keeping the drug suspended in the drug and slowing the release of the drug from the drug. As a result, we surprisingly found that the outer layer was a film made of cellulose lower alkyl ether, polyacrylic acid or a pharmaceutically acceptable salt thereof, and a plasticizer, and the inner layer was a drug-containing film and a blowing agent-containing film. When a drug in the form of a laminated film is administered orally, the gastric fluid that has passed through the outer film reaches the inner film containing the foaming agent and remains suspended in the stomach due to the carbon dioxide gas generated, causing the drug to pass through the outer film. The inventors have discovered that such a preparation is an extremely superior oral sustained-release preparation, and have arrived at the present invention. D. Constitution of the Invention In the present invention, the outer layer film (A) is a film consisting of cellulose lower alkyl ether, polyacrylic acid or a pharmaceutically acceptable salt thereof, and a plasticizer; cellulose lower alkyl ether,
The inner layer film (B) is a film consisting of a plasticizer and a drug, or a film consisting of cellulose lower alkyl ether, polyacrylic acid or a pharmaceutically acceptable salt thereof, a plasticizer, and a drug;
A film consisting of cellulose lower alkyl ether, polyacrylic acid or a pharmaceutically acceptable salt thereof, and a blowing agent is used as an inner layer film (C); an outer layer film (A), then an inner layer film (B), and then an outer layer film (C). An oral film-like sustained release preparation is provided, which is formed by laminating layers in the order of (A). The cellulose lower alkyl ether used in the outer layer film (A) and inner layer films (B) and (C) is
A plurality of hydroxyl groups of cellulose are at least partially substituted with the same or different lower alkyl ether groups. The lower alkyl group of the lower alkyl ether group may be substituted with a substituent. Preferred examples of such substituents include hydroxyl groups. Preferred examples of the optionally substituted lower alkyl group include a methyl group and a hydroxy lower alkyl group having 3 to 8 carbon atoms. Examples of the cellulose lower alkyl ether include methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Among these, hydroxypropylcellulose, ethylcellulose, or hydroxypropylmethylcellulose is preferred. Among them, it is more preferable to use hydroxypropyl cellulose. Hydroxypropylcellulose can be used with any molecular weight, but the viscosity of a 2% aqueous solution at 20°C is 3~3.
10000 centipoise, more preferably 1000-4000
It is even more preferable to use centipoise. The polyacrylic acid or its pharmaceutically acceptable salt used for the outer layer film (A) and the inner layer films (B) and (C) is used to form a film from a mixture of cellulose lower alkyl ether and a blowing agent. Desirably, the polyacrylic acid has a concentration of 0.2% as polyacrylic acid and a pH of 7 to 7.5, which is determined by the form of formation and sustained release properties of the drug.
In an aqueous solution of its sodium salt showing 25.0±0.5
Those exhibiting a viscosity of 200 to 200,000 centipoise when measured at °C are preferably used. The polyacrylic acid referred to in the present invention includes not only polyacrylic acid alone, but also polyacrylic acid containing a small amount (usually 20
Polymers containing other water-soluble polymers (up to % by weight) may also be used. Furthermore, polyacrylic acid refers not only to polyacrylic acid homopolymers, but also to copolymers obtained by copolymerizing methacrylic acid, styrene, vinyl ether monomers, etc. with acrylic acid. Naturally, this copolymerization ratio should be limited to a copolymerization ratio that can achieve the object of the present invention. Furthermore, the pharmaceutically acceptable salts of polyacrylic acid as used in the present invention include sodium salts, potassium salts, and the like. The blowing agent used in the inner layer film (C) includes carbonates or bicarbonates such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, and potassium hydrogen carbonate. Alternatively, mixtures of these salts and organic acids such as citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, and asmarbic acid may be used. For patients with achlorhydria, carbonate or bicarbonate and citric acid, tartaric acid, succinic acid,
It is best to use organic acids such as fumaric acid, maleic acid, and ascorbic acid in combination. Cellulose lower alkyl ether and polyacrylic acid or its pharmaceutically acceptable salt contained in the outer layer film (A), the inner layer film (C), and the inner layer film (B) when containing polyacrylic acid or a pharmaceutically acceptable salt. In the case of acceptable salts, it is determined by the film formation state and sustained release effect when forming a film consisting of a mixture of cellulose lower alkyl ether and polyacrylic acid or a pharmaceutically acceptable salt thereof.
The amount of polyacrylic acid or a pharmaceutically acceptable salt thereof is preferably 0.1 to 1000 parts by weight per 10 parts by weight of cellulose lower alkyl ether. More preferably, the amount is 0.1 to 100 parts by weight of polyacrylic acid or a pharmaceutically acceptable salt thereof per 10 parts by weight of cellulose lower alkyl ether. The inner layer film (B) may be produced without using polyacrylic acid or a pharmaceutically acceptable salt. The type and amount of plasticizer contained in the outer layer film (A) and inner layer film (B) vary depending on the ratio of cellulose lower alkyl ether and polyacrylic acid, film strength, and film flexibility. Phthalic acid esters such as dibutyl phthalate and butylphthalyl butyl glucorate; triacetin, propylene glycol, polyethylene glycol, rapeseed oil, etc. are preferably used, and the amount added is 1 to 50% by weight of the dry weight of the film layer. Preferably 5 to 25% by weight
It is more preferable that The amount of blowing agent in the inner layer film (C) is determined by the amount of carbon dioxide gas to be generated in the laminated film, but it is composed of cellulose lower alkyl ether and polyacrylic acid or a pharmaceutically acceptable salt thereof. The blowing agent is preferably used in an amount of 0.1 to 40 parts by weight, more preferably 0.5 to 20 parts by weight, per 10 parts by weight of the mixture. The active ingredient contained in the inner film (B) may be any drug for treating gastric diseases or systemic diseases for which the therapeutic effect is expected to be further increased than before by sustained release. Examples of drugs include the following: Digestion of gastrointestinal drugs (allantoin, aldioxa, alcloxa, pirenzepine hydrochloride, secretin, urogastrone, cetraxate, cimetidine, ranitidine, p-(trans-4-aminomethylcyclohexylcarbonyl)phenylpropionate hydrochloride, prostaglandins, etc.) Treatment for ulcers; synthetic aluminum silicate, natural aluminum silicate, dimagnesium aluminate silicate, bismuth magnesium aluminate silicate, dry aluminum hydroxide gel, hydrotalcite, magnesium aluminate metasilicate, magnesium silicate, magnesium oxide, Antacids such as magnesium silicate, heavy magnesium oxide, magnesium oxide, magnesium carbonate, and precipitated calcium carbonate; anti-pepsin drugs such as sucrose sulfate, hepstatin, and streptostatin; anti-inflammatory enzyme agents such as pepsin, diastase, and lipase) Central nervous system drugs (hypnotic sedatives such as diazepam and estazolam, anticonvulsants such as phenytoin, meprobamate, and nitrazepam; acetaminophen, ethenzamide, salicylamide, pentazocine, clofezone, indomethacin, ketoprofen, naproxen, flubiprofen, diclofenac, Kridanak,
Arclofenac, flufenamic acid, mefenamic acid, sulindac, piroxicam, menthol, camphor, D-penicillamine, dexamethasone, triamcinolone, betamethasone,
Antipyretic, analgesic, and antiinflammatory drugs such as corticosteroids including brednisolone; psychoneurotic drugs such as chlorpromazine; antivertigo drugs such as isoprenaline, petahistine mesylate, and scopolamine; general anesthetics, etc.) Allergy drugs or antihistamines (diphenhydramine, etc.) , periactin, etc.), cardiovascular drugs (cardiac drugs such as digitalis and ubidecarenone; β-blockers or antiarrhythmic drugs such as pindolol, propranolol hydrochloride, alprenolol hydrochloride, oxprenolol hydrochloride; theophylline, trichlormethane, etc.) Diuretics such as thiazide, spironolactone, methyclothiazide, metolazone, tripamide, furosemide, penfluzide; blood pressure sclerosing agents such as dihydropyridine derivatives including reserpine, clonidine hydrochloride, methyldova, hydralazine, syrosingobine, recinamine, cinnarizine, brazosin hydrochloride, nifedipine; rutin, Vascular reinforcement agents such as carbazochrome; vasoconstrictors such as dihydroergotamine mesylate, dihydroergotoxine mesylate; nitroglycerin, isosorbitol nitrate, dilazeb hydrochloride, nifedipine, diltiazem hydrochloride, trimetazidine hydrochloride,
Coronary vasodilators such as trapidil and dipyridamole; peripheral vasodilators such as inositol and hexanicotinate; arteriosclerotic agents such as clofibrate; pentoxifylline, cytochrome C, dextran sodium sulfate, pyrithioxine, citicoline, nicardipine hydrochloride, Dopamine hydrochloride, prostaglandins, prostacyclic acid, dobutamine hydrochloride, alprostadil,
Ifenprodil tartrate, etc.). Respiratory agents (antitussive expectorants such as efuedrine, codeine, bromhexine; isoproterenol, dextromethylfan, orciprenaline, ipratrobium promide, cromoglycic acid, etc.), hormonal or antihormonal agents (human growth hormone, etc.) , pituitary hormones such as corticotropin, oxytocin, vasopressin, and brothyrelin tartrate; male hormones such as testostyron; female hormones such as progesterone and estradiol; salivary gland hormones, thyroid and parathyroid hormones, anabolic steroids, adrenal hormones, etc.). Urogenital drugs (such as uterotonic agents such as dinoprost and dinoprostone), metabolic drugs (alfacalcidol, 1.24
-vitamins such as dihydroxycholecalciferol and mecobalamin; tonic and altering agents; glutathione, ATP, aprotiline, capexate mesylate, etc.), drugs for ulcers (krestin, ancitabine, mitomacin, methotrexate, carbocone, cytarabine, picibanil, tegafur) 5-fluorouracil derivatives including carmofur, 5
-fluoro-2'-deoxyuridine and its derivatives, etc.), antibiotics (tetracycline antibiotics, penicillin antibiotics, cephalosporin antibiotics, etc.), chemotherapeutic agents (clotrimazole, pyrrolnitrine, alaphosphalin, sulfur drugs, etc.) The amount of such drug is appropriately determined depending on the strength of activity of each drug. The oral film-like sustained release preparation provided by the present invention with excellent gastric retention is produced as follows. That is, the outer layer film (A) is prepared by adding a plasticizer to an organic solution of cellulose lower alkyl ether, polyacrylic acid or a pharmaceutically acceptable salt thereof such as methanol or ethanol, and pouring the mixture onto a Teflon plate with a shear plate or frame. The solvent is distilled off to form a film. The inner layer film (B) is made by adding a drug to the solution used to create the outer layer film (A), or adding a drug to an organic solution consisting of cellulose lower alkyl ether and a plasticizer, and placing it on a Teflon plate with a shear plate or frame. The solution is poured and the solvent is distilled off to form a film. The inner layer film (C) is made by suspending a blowing agent in an organic solution of cellulose lower alkyl ether, polyacrylic acid, or a pharmaceutically acceptable salt thereof, pouring it onto a Teflon plate with a frame, and distilling off the solvent to form a film. do. The outer film is then formed using an organic solution of cellulose lower alkyl ether and polyacrylic acid or a pharmaceutically acceptable salt thereof as a sizing agent.
Inner layer films (B) and (C) are sandwiched between (A) and adhered to form a four-layer laminated film, that is, outer layer film (A), then inner layer film (B), (C), then outer layer film ( A film-like preparation is formed by laminating layers in the order of A). The size of the preparation is arbitrary, but for example, the outer layer film (A) is a square with an area of 16 cm ² , the inner layer film (B),
(C) is preferably a square with an area of 6.25 cm ² . E. Effects of the Invention The effects and characteristics of the formulation provided by the present invention described above include the following. 1. It remains suspended in the stomach for a long time, and therefore it is possible for gastric topical drugs to act directly and locally at high concentrations for a long time.Also, when the absorption site is limited to the upper small intestine, the drug is released. The ability to deliver the drug at a constant concentration increases the rate of absorption and eliminates the risk of the drug passing through the absorption site before being released. 2. Film strength and drug release can be suppressed depending on the type and combination of cellulose lower alkyl ethers. 3. The drug release rate can also be controlled to meet therapeutic objectives by varying the quantification of cellulose lower alkyl ether and polyacrylic acid or its pharmaceutically acceptable salt. 4. The drug is present in a separate film;
Chemical stability is not compromised by blowing agents such as sodium bicarbonate. F. EXAMPLES The present invention will now be explained in detail with reference to Examples, but the present invention is not limited thereto in any way. Example 1 A laminated film containing sodium riboflavin phosphate was prepared as follows. (1) Creation of film layer (A) 3% hydroxypropyl cellulose (trade name
HPC-H) and 3% polyacrylic acid (trade name Carbopol 934) in ethanol solution in a ratio of 1:2 by weight, and further added 0.5% Macrogol 400 based on the total weight of the solution. the
Pour 10g evenly into a 6cm ² tray,
After drying and distilling off the ethanol, the film was cut into squares of 4 cm on each side to obtain a film layer (A) with a thickness of 70 to 90 μm. (2) Creation of film layer (B) Add 270 mg of sodium riboflavin phosphate to 10 g of a solution with the same composition as film layer (A), and use this total amount to create a film layer with a side of 2.6 cm in the same manner as in (1). I got (B). One sheet of this film contains 30 mg of sodium riboflavin phosphate. (3) Creation of film layer (C) 2% hydroxypropylcellulose (trade name
HPC-H) and 2% polyacrylic acid (trade name Carbopol 934) in ethanol solution are mixed in a ratio of 1:2 by weight, 2.4 g of sodium hydrogen carbonate is further suspended in this 24 g, and the total amount is
The mixture was poured onto a Teflon plate with a frame of 96 cm ² , and after drying and distilling off the ethanol, it was cut into squares of 2.6 cm on each side to obtain a film layer (C). (4) Creation of laminated film Sandwich film layers (B) and (C) between two film layers (A) and add 3% hydroxypropyl cellulose (trade name HPC-H) and 3% polyacrylic acid (trade name Carboxylic acid). Pall 934) ethanol solution was mixed in a ratio of 1:2 by weight to make the film layer.
The paste was applied uniformly around (A), and after drying, the glue-applied portion was heat-pressed to produce a four-layer laminated film as shown in the figure containing 30 mg of riboflavin sodium phosphate. Example 2 Using the laminated film prepared in Example 1,
Dissolution tests in vitro were conducted three times to confirm floating properties and sustained release properties. (Conditions) Equipment: Japanese Pharmacopoeia X dissolution tester Method: 2nd method (paddle method) Test solution: 1st solution 800ml Temperature: 37℃ Rotation speed: 100rpm

[Table] Floating on the surface.
Example 3 A laminated film containing cinnarizine was prepared as follows. (1) Creation of film layer (A) Mix an ethanol solution of 3% hydroxypropyl cellulose, 3% polyacrylic acid, and 3% ethyl cellulose in a ratio of 1:2:1 by weight, and then add Add 0.5% Macrogol 400 and pour 10 g of it evenly into a 60 cm ² glass tray. After drying and distilling off the ethanol, cut it into squares with sides of 2.5 cm and thickness.
A film layer (A) of 70 to 90 μm was obtained. (2) Creation of film layer (B) 1.0% macrogol 400 for 16g of ethanol solution of 3% hydroxypropyl cellulose
2.1 g of cinnarizine was added, and the entire amount was poured onto a Teflon plate with an area of 96 cm ² to remove the ethanol by dry distillation.
The film layer (B) was obtained by cutting into cm squares. One sheet of this film contains 50 mg of cinnarizine. (3) Creation of film layer (C) Mix an ethanol solution of 2% hydroxypropyl cellulose, 2% polyacrylic acid, and 2% ethyl cellulose in a ratio of 1:2:1 by weight,
An additional 2.4 g of sodium hydrogen carbonate was suspended in this 24 g, and the entire amount was poured onto a Teflon plate with a frame of 96 cm ² , and after dry distillation of the ethanol,
Cut into squares with sides of 1.5 cm and film layer (C)
I got it. (4) Preparation of laminated film Sandwich film layers (B) and (C) between two film layers (A), add 3% hydroxypropyl cellulose,
% polyacrylic acid and 3% ethyl cellulose in ethanol at a ratio of 1:2:1 to make a glue, apply it uniformly around the film layer (A), and after drying, heat and press the glue-applied area. A four-layer laminated film as shown in the figure containing 50 mg of cinnarizine was prepared. Example 4 Using the laminated film prepared in Example 1,
An in vitro dissolution test was conducted to confirm floating properties and sustained release properties. (Conditions) Equipment: Japanese Pharmacopoeia X dissolution tester Method: 2nd method (paddle method) Test solution: 1st solution 800ml Temperature: 37℃ Rotation speed: 100rpm (Results)

【table】

[Table] Floating on the surface.
Example 5 The laminated film prepared in Example 3 was orally administered to three beagle dogs, and the sustained release of the drug was confirmed by measuring the blood concentration.

【table】

【table】 [Brief explanation of the drawing]

The figure shows an oral film sustained release preparation of the present invention. 1 in the diagram is the outer layer film (A), 2 is the inner layer film
(B), 3 shows the inner layer film (C).

[Claims]

1 Formula as active ingredient (In the formula, R ₁ and R ₂ are H or C ₁ -C ₁₈ acyl, and R ₃ is H, C ₁ -C ₁₈ acyl or

An antitumor pharmaceutical composition comprising a compound represented by the formula: or a physiologically compatible salt thereof. 2. The composition of claim 1, wherein the compound is 2-β-D-ribofuranosylthiazole-4-carboxamide. 3 The above compound is an acyl ester of 2-β-D-ribofuranosylthiazole-4-carboxamide.

Claims (1)

4 The blowing agent in the inner layer film (C) is carbonate,
Claims 1 to 3 are bicarbonates, or mixtures of carbonates or bicarbonates and organic acids.
The oral film-like sustained release preparation according to any one of the above items. 5. Claims 1 to 4, wherein the cellulose lower alkyl ether in the outer layer film (A) and the inner layer films (B) and (C) is hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, or ethyl cellulose. The oral film-like sustained release preparation according to any one of the above. 6 The cellulose lower alkyl ether in the outer layer film (A) and inner layer films (B) and (C) is hydroxypropyl cellulose, and 2% at 20°C
The oral film-like sustained release preparation according to any one of claims 1 to 5, which exhibits a viscosity of 3 to 10,000 centipoise in an aqueous solution. 7 The polyacrylic acid in the outer layer film (A), inner layer film (B), and (C) is an aqueous solution of its sodium salt with a concentration of 0.2% as polyacrylic acid and a pH of 7.0 to 7.5, and is 25.0 ± 0.5. The oral film-like sustained release product according to any one of claims 1 to 6, which exhibits a viscosity of 200 to 200,000 centipoise when measured at °C.