JPH057365B2 - - Google Patents

Description

[Detailed description of the invention]

<Industrial Application Field> The present invention relates to a long-acting pharmaceutical formulation. More specifically, the present invention relates to a long-acting pharmaceutical preparation containing a drug in the outer shell of a solid molded foamed ethyl cellulose or inside the molded product. <Prior Art> It is obvious that sustaining the effects of drugs is significant in terms of drug treatment of diseases. Some drugs, after being absorbed, are not easily metabolized or excreted and their efficacy persists. For example, warfarin is said to have a biological half-life of 46 hours. Such drugs have long-lasting efficacy due to their inherent properties. However, after many drugs are absorbed, they are easily metabolized by enzymes and excreted through the kidneys, and their effects do not last for a long time. In order to maintain the effects of these drugs, various techniques have been devised and
It has been implemented. First, when administering a drug orally, many methods have been proposed to control the release of the drug from the preparation and adjust its absorption, thereby keeping the drug concentration in the body above the effective concentration for a long period of time. Some of them have been put into practical use. Second, methods have been implemented in which drugs are administered intravenously over a long period of time.
Third, by changing the route of drug administration,
Methods have been proposed to avoid metabolism in the liver and maintain drug efficacy, and transdermal administration has attracted particular attention in recent years, and some have been put into practical use. Among these methods, the second method, intravenous drip, can usually only be performed in medical facilities such as hospitals, and the third method, transdermal administration, is limited to drugs that can be absorbed through the skin. These two methods are not common because they have certain limitations. On the other hand, the first method, prolonging the efficacy of orally administered drugs, is applicable to many drugs;
In addition, it is simple and more common because patients only need to take it internally, and if there is a good method, it would be of great significance. Conventionally, many methods have been proposed for prolonging the efficacy of orally administered drugs. This method is broadly classified into two types. First of all, it is a method of modifying the drug itself to adjust its solubility and prolong its dissolution and absorption in the gastrointestinal tract.Specifically, it is a method for preparing poorly soluble drug salts or drug crystal formulations. Examples of methods include adding . The second method is to maintain the dissolution and absorption of the drug in the gastrointestinal tract by utilizing the effects of additives without modifying the drug itself. Specifically, the drug is coated with an appropriate film. Examples include a method in which the drug is contained in a suitable matrix, or a method in which the drug is coexisted with an additive that has high adhesiveness to the gastrointestinal mucosa. However, when many of the above-mentioned methods that have been proposed so far are actually administered to a living body, the movement speed in the gastrointestinal tract is high, the pH change in the gastrointestinal tract is large, the influence of food is large, and these problems occur. Factors that vary greatly from person to person, or for some drugs, the site where the action is expected to occur or the site where it is absorbed may vary.
Although it is limited to the stomach, upper small intestine, etc., it is not as effective as expected in vitro due to the fact that orally administered preparations often pass through these areas. That is the reality. Therefore, it is desired to provide a preparation that maintains its efficacy despite many changes in physiological conditions and localization of the site of action and absorption of the drug. On the other hand, an oral solid drug has been proposed that uses a buoyant material to float and remain in the stomach for a long period of time, and continuously releases the active drug during that period (Japanese Patent Application Laid-Open No. 1983-1999-
Publication No. 12411). However, although this specification mentions foamed grains such as foamed polystyrene or foamed rice as examples of materials that have buoyancy in the stomach, there is no mention of cellulose ether derivatives such as foamed ethyl cellulose. Not yet. <Problems to be Solved by the Invention> The present inventors have solved the problem due to fluctuations in physiological conditions between patients (“individual differences”) and fluctuations in physiological conditions of the same patient (for example, “day-to-day fluctuations”). As a result of intensive research into the development of a formulation that has long-lasting medicinal efficacy and has sustained medicinal efficacy regardless of the localization of the drug's action site or absorption site, we have developed a solid formulation using foamed ethylcellulose and its outer shell. Alternatively, the inventors have discovered that the desired objective can be achieved by incorporating a drug into foamed ethyl cellulose, and have thus arrived at the present invention. <Means for Solving the Problems> That is, the present invention is a long-acting pharmaceutical preparation comprising a solid molded product of foamed ethyl cellulose and a drug contained in its outer shell and/or inside thereof. When the drug is contained inside the foamed ethylcellulose solid molded product as in the present invention, the diffusion of the drug within the foamed ethylcellulose is slow, so that its elution from the preparation is delayed accordingly. On the other hand, when a drug is contained in the shell of foamed ethylcellulose, if the drug itself elutes slowly, the drug can be coated or attached to the foamed ethylcellulose, but if the drug itself elutes quickly, the drug can be coated or attached to the foamed ethylcellulose. When this is done, additives that have the effect of delaying elution, such as coating agents, may be present. According to the formulation of the present invention, after oral administration, the formulation remains suspended in the stomach for a long time, during which time the drug is continuously released. Therefore, it is not only effective for drugs that have an effect in the stomach or are absorbed from the stomach and have post-absorption effects, but also for drugs that have an effect in the duodenum, small intestine, large intestine, etc. It can also be used for drugs that are absorbed from there and exhibit post-absorption effects. Ethylcellulose for obtaining the expanded ethylcellulose used in the present invention is an ethoxy derivative of cellulose with an ethoxyl group content of 44.0% to 52.0%, and an ethoxyl group content of 45.0% to 52.0%.
50.0% is more preferable (for example, Dow Chemical Company, ethyl cellulose Medium type,
Standard type; K type manufactured by Hercules Co., Ltd.
N type, T type, etc. are preferred. ) Its molecular weight is preferably in the range of 1 to 10.000 cps in terms of viscosity;
The range of ~1000 cps is more preferable, and the range of 3~500 cps is even more preferable. The foamed ethylcellulose used in the present invention is obtained by foaming the above-mentioned ethylcellulose. As a foaming method, ethyl cellulose is heated and pressurized with an inert gas, such as nitrogen gas, and then
There is a well-known method of suddenly releasing the pressure (USP 2531665).Also, it can be obtained by applying pressure and heat to ethyl cellulose in the presence of ethyl alcohol to gel it, and then suddenly releasing the pressure. case,
Ethanol also acts as a blowing agent). Also,
It can also be obtained by adding a foaming agent and heating and foaming. The foamed ethyl cellulose used in the present invention is solid, preferably formed into small spheres or pellets. The ethyl cellulose foamed by the above method is molded into small spheres or pellets by a conventional method. The molding may be carried out by pouring gelled ethyl cellulose under heat and pressure into a suitable mold, and then removing the pressure and foaming the mold. Alternatively, the sheet-like foam may be molded by an appropriate method. The drug used in the present invention is one that exhibits its action in the stomach and has a preferable duration of action, i.e., an anti-ulcer agent such as a gastric acid secretion inhibitor, a neutralizing agent, or an anti-pepsin agent; drugs that are specifically absorbed and exhibit post-absorption effects;
Alternatively, drugs that have an effect in the stomach, or that are not absorbed from the stomach but have an effect in the duodenum, small intestine, large intestine, etc., or have an after-effect after being absorbed, and it is preferable to have a sustained action. be. Examples of these drugs may include the following drugs: Antipyretic, analgesic and anti-inflammatory agents such as mefenamic acid, acemethacin, indomethacin, alclofenatsuta, ibuprofen, tiaramide hydrochloride, ketoprofen, diclofenac sodium, sulindac, naproxen, fenbuen, flurbiprofen, mepirizole, piroxicam; acebutolol hydrochloride, alkaline hydrochloride Antiarrhythmic drugs such as Prelol, indenolol hydrochloride, oxprenolol hydrochloride, carteolol hydrochloride, propranolol hydrochloride, pindolol, disopyramide; blood pressure lowering drugs such as clonidine hydrochloride, bunitrol hydrochloride, prazosin hydrochloride, captopril, metoprolol tartrate, methyldova, betanidine sulfate, etc. Agents: ethaphenone hydrochloride, oxyphedrin hydrochloride, carbochromene hydrochloride, dilazeb hydrochloride, diltiazem hydrochloride, trimetazidine hydrochloride, verabamil hydrochloride, dipyridamole, isosorbide nitrate, trapidil,
Vasodilators such as nicorandil, nifedipine, inositol hexanicotinate, isoxsuprine hydrochloride, nimethate citrate, citalanderate, cinnarizine; Arteriosclerotic agents such as clofibrate, sinfibrate, elastase, soisterol, nicomol; hydrochloric acid Cardiovascular agents such as nicardibine, nimodipine hydrochloride, meclofenoxate hydrochloride, cytochrome C, ifenprodil tartrate, tocopherol nicotinate, pentoxifylline; chlorprenaline hydrochloride, pirbuterol hydrochloride,
bitolterol mesylate, salbutamol sulfate,
Antitussive and expectorant agents such as terptaline sulfate, hexoprenaline sulfate, dimemomorphan phosphate, ambroxol hydrochloride, L-ethyl cysteine hydrochloride, trimethoquinol hydrochloride, bromhexine hydrochloride, theophylline, tranilast; aluminum aceglutamide, L-glutamine, p- (trans-4-aminomethylcyclohexanecarbonyl)-phenylpropionate hydrochloride, cetraxate hydrochloride, pirenzepine hydrochloride, gefalnate, cimetidine, glycopyrronium bromide, atropine sulfate, scopolamine hydrobromide,
Benactidine hydrochloride, propantheline bromide, sulpiride, 17,20-dimethyl-6-oxoprostaglandin E ₁ methyl ester, 6-oxoprostaglandin E ₁ , 15-methyl-prostaglandin E ₂ , 16-methyl- Prostaglandins such as 16-hydroxy-15-dehydroxyprostaglandin E ₁ methyl ester, 7-thiaprostaglandin E ₁ methyl ester, 17,20-dimethyl-7-thiaprostaglandin E ₁ methyl ester, etc. antiulcer agents; synthetic aluminum silicate, natural aluminum silicate, dimagnesium aluminate silicate, magnesium bismuth aluminate silicate, dry aluminum hydroxide gel, hydrotalcite, magnesium aluminate metasilicate, magnesium silicate, magnesium oxide, Antacids such as heavy magnesium oxide, magnesium hydroxide, magnesium carbonate, and precipitated calcium carbonate; Anti-pepsin drugs such as sucrose sulfate, hepstatin, and streptostatin; Anti-inflammatory enzymes such as pepsin, diastase, and rebase; Chymotrypsin and streptokinase , lysozyme chloride, seaprose, serrapeptase, pronase, bromelain, and other enzyme preparations; methotrexate, carbocone, carmofur, tegafur, fluoraucil, and other anti-cancer agents; oxacillin, phenecillin potassium, amoxicillin, ampicillin, cephalexin, cefrazine, trimazole, pyrrolnitrine,
Chemotherapy agents such as alaphosphalin and sulfur drugs; anti-inflammatory steroids such as hydrocortisone, prednisolone, triamcinolone, dexamethasone, and betamethasone; antihistamines such as diphenhydramine hydrochloride and chlorpheniramine maleate; urinary tract drugs such as urinary flavoxate hydrochloride; Hormonal or antihormonal agents such as human growth hormone, corticotropin, oxytocin, vasopressin, proteresone tartrate, testrosterone, progesterone, estradiol; diazepam, estazolam, phenytoin, meprobamate, nitrazepam, chlorpromazine, isoprenaline, betahistine mesylate, scopolamine, etc. There are drugs for the central nervous system. The content of such drugs in the preparation is appropriately determined depending on the strength of activity of each drug. The drug of the present invention is contained in the outer shell of the foamed ethyl cellulose solid molding and/or inside the shell. When the drug is to be contained in the outer skin, the drug may be coated or attached to the foamed ethyl cellulose solid molded product by an appropriate method. Specifically, the drug is coated or adhered to the foamed ethyl cellulose solid molded product using, for example, a fluidized bed coating device, a high-speed stirring granulation device, or a centrifugal rolling granulation device. In that case, the drug is dissolved in a suitable solvent if necessary. Further, if necessary, it is coated or attached to the foamed ethyl cellulose solid molded product together with other additives. Other additives include excipients, binders,
Examples include coating agents, stabilizers, coloring agents, bridging agents, and the like. Excipients include microcrystalline cellulose, lactose, starch, calcium hydrogen phosphate, and the like. Examples of the binder include starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, and the like. Coating agents include methacrylic acid ethyl acrylate copolymer, methacrylic acid methyl methacrylate copolymer, carnauba wax, glycerin fatty acid ester carbopol, cellulose acetate phthalate, hydroquinepropyl methyl cellulose phthalate shellac, paraffin, hydroxypropyl cellulose, hydroxy Examples include propylcellulose. Examples of the stabilizer include preservatives such as paraoxine benzoate, and antioxidants such as butylated hydroxytoluene and ascorbic acid. Examples of colorants include caramel, tar-based pigments, and the like. Examples of flavoring agents include sucrose, fructose, multitrol, and glycyrrhizin. If necessary, the drug may first be coated or attached to the foamed ethyl cellulose solid molded product, and then the other additives mentioned above may be further coated or attached thereon. Further, one or more foamed ethyl cellulose solid molded products are contained per unit particle. When a drug is contained inside the foamed ethylcellulose solid molded product, the drug may be added at the same time as the ethylcellulose is foamed.
In that case, the drug may be dissolved in a solvent or dispersed as fine particles. Furthermore, the above-mentioned stabilizers, colorants, etc. may be added as necessary. The preparations of the present invention produced in this way can be used as powders, fine granules, granules, etc. depending on their size and shape.
It is used as a tablet, but if necessary, it may be filled into hard gelatin capsules and used as a hard capsule. <Effects of the Invention> According to the sustained-activity pharmaceutical preparation of the present invention, the drug remains suspended in the stomach for a long period of time, and the drug is continuously released during that period, making it possible to maintain the drug's efficacy, and to achieve a new sustained-activity effect. The present invention is of great significance as it provides a type of pharmaceutical composition. <Examples> The present invention will be explained in more detail below using examples. Example 1 (i) Preparation of expanded ethyl cellulose Expanded ethyl cellulose spherules were manufactured according to a known method (USP 2531, No. 665). i.e., ethylcellulose particles (50μ in diameter)
Below) 10g was heated to 110℃ in an autoclave,
Pressurize with nitrogen gas at approximately 4000lbs/vg inch. Then, it is left to cool under pressure, and once cooled, the pressure is released. Next, the temperature is raised to about 150° C. under nitrogen gas pressure of about 1000 lbs/sg inch, and maintained for about 5 minutes. after that,
The pressure is suddenly released, the foam is allowed to cool, and the diameter is approximately 1.0-
2.0 mm expanded ethyl cellulose spherules were obtained. The density was approximately 0.6 g/cm ³ . (ii) Weigh out 30g of the expanded ethylcellulose spherules (about 1.0-2.0mm in diameter) produced in (i), place them in a fluidized bed coating device (FLO-I model manufactured by Okawara Seisakusho), and add nifedipine and hydroxypropylcellulose. Coat with ethyl alcohol solution (nifedipine concentration 5%, hydroxypropyl cellulose concentration 0.25%) using a spray gun,
Granules containing mg were obtained. (iii) 1 g of the granules in (ii) was administered to a beagle dog, blood was collected at a certain time after administration, and the concentration of nifedipine in the blood was determined by ECD gas chromatography. At the same time, as a control, 3 capsules of commercially available nifedipine soft capsules (30
mg) was administered to beagle dogs, and the blood nifedipine concentration was measured in the same manner. The results are shown in Table 1.

[Table] As shown in Table 1, with commercially available products, the blood concentration quickly decreases, whereas with the preparation of the present invention, the blood concentration can be maintained high for a longer period of time. Recognize. (iv) Take 100 mg of the granules in (ii) and administer by force orally to white native rabbits that have been fasted overnight. Two hours after administration, kill the rabbits, open the abdomen, remove the stomach, and examine its contents with the naked eye. Observation was made to check for the presence of granules. Also,
The amount of nifedipine in the gastric contents was determined by high performance liquid chromatography, and the residual rate in the stomach relative to the dose was determined. At the same time, as a control, 100 mg of commercially available nifedipine fine granules was taken and tested in exactly the same manner as above, observing the residual state of the preparation in the stomach 2 hours after administration and measuring the residual rate of nifedipine in the stomach. Ivy. The results are shown in Table 2.

[Table] Example 2 15 g of foamed ethyl cellulose in the form of egg-shaped pellets (weight 30 mg per unit) with a minor axis of 6 mm and a major axis of 9 mm produced in the same manner as in Example 1 was taken and placed in a fluidized bed coating device (FLO). - Type I: Okawa Seisakusho), and coated with an aqueous solution of glycopyrronium bromide and hydroxypropyl cellulose (glycopyrronium bromide, concentration 10%, hydroxypropyl cellulose concentration 0.05%) using a spray gun, Glycopyrronium bromide is coated to 6 mg per unit dosage. Then,
An emulsion of methacrylic acid ethyl acrylate copolymer (Oidofugit L30D-55) is coated using a spray gun until the weight of the unit dosage increases by 4 mg. Example 3 After dissolving 10 g of ethyl cellulose and 1 g of indomethacin in ethyl alcohol, the solution was kept at about 70° C. for several days to remove the solvent, thereby producing an ethyl cellulose block containing indomethacin. This block is heated and pressurized in the same manner as in Example 1 to impregnate it with nitrogen gas. After being allowed to cool under pressure, the mixture was further heated to about 150° C. under pressure to form a gel, and then the pressure was rapidly released and allowed to cool to obtain expanded ethylcellulose pellets containing indomesacin. Comparative Example 1 A granule (nifedipine 30 mg/g) was prepared by coating the surface of rice foamed by heat treatment with nifedipine (nifedipine 30 mg/g), and 1 g of the granule was administered to a beagle dog in the same manner as in (iii) of Example 1. Blood nifedipine concentration was measured. The results are shown in Table 3. The granules used as a control were manufactured as follows. That is, we weighed out about 30 g of foamed rice (with a diameter smaller than about 5 mm) and applied it to a fluidized bed coating device (Model FLO-I: manufactured by Okawara Seisakusho).
and coated with an ethyl alcohol solution of nifedipine and hydroxypropyl cellulose (nifedipine concentration: 5%, hydroxypropyl cellulose concentration: 0.25%) using a spray gun to obtain granules containing 30 mg of nifedipine per gram.

[Table] Comparative Example 2 1 g of the granules prepared in (ii) of Example 1 was administered to five beagle dogs once a day for one week. Feed after drug administration
Gave 30 minutes. Observations were made for 1 week during administration and for 3 days after administration, but all of the animals were healthy and there was no change in the condition of their feces. At the same time, 1 g of granules made from expanded polystyrene spherules of the same size instead of the expanded ethyl cellulose spherules in (ii) were similarly administered to five beagle dogs. In the group that received granules made of expanded polystyrene microspheres, one of the five dogs developed constipation on the fifth day of administration. The beagle remained constipated on the 6th day, so a laxative (Laxoberone) was administered to the dog, which defecated, but a lump of polystyrene foam was found in it. No abnormalities were observed in the other four animals. As is clear from Comparative Examples 1 and 2, we produced internally sold solid preparations with foamed polystyrene or foamed rice as the core material and coated the drug on the outer skin, and as a result of examining their sustained release effects, we found that foamed polystyrene was used. In some cases, constipation occurred in animal experiments (beagle dogs), and although the elution of the drug was delayed when foamed rice was used, it is probably due to rapid disintegration of the drug after entry of digestive juices. It became clear that the sustainability was not sufficient.

Claims (1)

[Scope of Claims] 1. A long-acting pharmaceutical preparation comprising a solid molded product of foamed ethyl cellulose and a drug contained in its outer shell and/or its interior. 2. Sustained activity according to claim 1, wherein the solid molded foamed ethyl cellulose is a solid molded product obtained by foaming ethyl cellulose having a viscosity in the range of 1 to 10,000 cps and molding it into a solid shape. type pharmaceutical formulation. 3. The sustained-activity pharmaceutical preparation according to claim 1 or 2, wherein the solid molded foamed ethyl cellulose is in the form of small spheres or pellets.