JPH03148215A - Laminated formulation - Google Patents

Abstract

PURPOSE:To obtain sustained release laminated formulation of flavoxate hydrochloride useful for medical drug having stabilized release of drug, safety and reduced bitterness, etc., in administration by laminating sustained release part and quick release part respectively comprising specific substances. CONSTITUTION:Two parts composed of a sustained release part comprising three layers of A) flavoxate hydrochloride-containing layer, B) intermediate layer and C) enteric skin substance layer and a quick release part comprising D) flavoxate hydrochloride-containing layer and E) acid-soluble skin substance layer are laminated to afford the aimed formulation. Combination of hydroxypropyl methyl cellulose acetate succinate as the C-layer component and starch as the B-layer component is effective. Mixing weight ratio of flavoxate hydrochloride in the quick release part and in the sustained release part is 1:0.5-4, preferably 1:1-4, especially 1:2.3.

Description

[Detailed description of the invention] [Industrial application field]

The present invention relates to a laminated type sustained release preparation of frapoxate hydrochloride in which an immediate release part is formed outside the sustained release part. More specifically, it consists of an immediate-release portion that dissolves quickly in the stomach and a controlled-release portion that is difficult to dissolve in the stomach and reaches the intestines, and when administered orally to humans. This allows the release of the component to be sustained over a long period of time, thereby making the therapeutic effect effective. Therefore, the present invention finds use in the pharmaceutical field.

[Conventional technology]

Conventionally, flavoxate hydrochloride preparations are sugar-coated tablets coated with sucrose, etc., or hydroxypropylcellulose,
Film-coated tablets or tablets coated with hydroxypropyl methylcellulose or the like are commercially available and widely used. These flavoxate hydrochloride preparations have been shown to have excellent therapeutic effects on frequent urination and residual urination; however, they are rapidly absorbed from the gastrointestinal tract and have a short biological half-life of 1.2 hours, so their efficacy may not last long. The time required is short, 4 to 5 hours, and the situation is such that the drug must be taken three times a day. For this reason, especially considering that there are many elderly people who take this type of drug, they are accompanied by pain such as sleep disturbance due to nocturnal urination. Under these circumstances, there is a demand for a hydrochloric acid flavoxate preparation that exerts its medicinal effect immediately after administration and has a long duration of medicinal effect, but no useful preparation has yet appeared. JP-A-63-154619 describes that immediate-release granules containing flavoxate hydrochloride and granules coated with an enteric coating material are mixed in a fixed ratio to prepare a sustained-release preparation. However, according to the detailed research conducted by the present inventors, an insolubilization phenomenon of the film due to the interaction between flavoxate hydrochloride and most enteric coating substances has been observed, and as a result, the conditions under which the enteric coating substance dissolves are observed. It has been found that the original smooth dissolution of the film is hindered even at lower temperatures, resulting in problems with the release properties of flavoxate hydrochloride, and it is difficult to say that this is a sustained release preparation that is necessarily satisfactory. Furthermore, it is a known fact that a drawback of this type of preparation is that the composition ratio of both granules in a dosage unit is difficult to maintain and can vary widely. The reason seems to be that there is difficulty in the mixing operation due to factors such as differences in specific gravity, size, surface condition, and chargeability of both granules, but in any case, the variation in composition ratio is due to the difference in the specific gravity, size, surface condition, and chargeability of the two granules. This is a defect that impairs the reliability and usefulness of Furthermore, as is well known, flavoxate hydrochloride has a strong bitter taste, so sufficient consideration must be given to masking when taking it.

[Problem to be solved by the invention]

In view of the above circumstances related to flavoxate hydrochloride, the present inventors have conducted intensive research and have developed a special membrane layer and a specific enteric coating to avoid contact between flavoxate hydrochloride and enteric coating material. By discovering the composition of the substance, problems related to insolubilization of the coating material and drug release properties were solved; problems related to variations in composition ratio were solved by integrating the immediate release part and sustained release part; By coating with a soluble coating substance, compliance-related problems such as bitterness can be improved, leading to the completion of the present invention. That is, the purpose of the present invention is to solve the above-mentioned problems associated with flavoxate hydrochloride, and to provide a sustained release preparation of flavoxate hydrochloride that does not have problems with compliance during or after administration and has a stable therapeutic effect.

[Means to solve the problem]

In the present invention, the immediate release portion is the portion that quickly releases the drug in the stomach after administration and exhibits initial drug efficacy, and the sustained release portion is the portion that does not release the drug in the stomach but releases the drug after the pH reaches the upper part of the small intestine. This is the part that exhibits medicinal effects. The present invention will be described in detail below, mainly focusing on the granule type side edges. However, the present invention is not limited to these side edges. In order to obtain the flavoxate hydrochloride sustained release laminated preparation of the present invention, the sustained release portion is first prepared. The method for adjusting the sustained release portion is not particularly limited, and conventional methods such as extrusion granulation, crushing granulation, transfer granulation, etc. can be used, but the simplest example is centrifugal flow coating. There is a method in which flavoxate hydrochloride is sequentially coated onto commercially available spherical particles using a granulation device. Specifically, spherical granules are put into a centrifugal fluid coating granulator and rotated by centrifugal force (due to the rotation of the rotor), while at the same time air is blown out from between the side wall of the granulator and the rotating body (slit). Aqueous or organic solvent solutions of sucrose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, etc. are sprayed from a spray gun located above the flow to a controlled height, and at the same time a granulator is A mixed powder of corn starch containing hydrochloric acid flavoxate, lactose, low-substituted hydroxypropyl cellulose, crystalline cellulose, talc, etc. is introduced from the powder inlet located above to perform granulation. This is then coated with an enteric coating material to control drug release. Enteric coating materials include cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate,
Hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, methacrylic acid ethyl acrylate copolymer, methacrylic acid methyl methacrylate copolymer, etc. are used, but the present inventors have developed granules coated with these enteric coating materials. Dissolution test using second liquid or pH change dissolution test over time (Kazuyuki Ueno, Recent Formulation Technology and Its Applications P, 12
4. When conducting tests such as Iyaku Journal Co., Ltd., we found that most enteric coated coating materials experience delayed film dissolution and associated drug release delays, and that insolubilized substances remained for a long period of time. . The cause is unknown, but in any case, the problem with the release control mechanism significantly impedes its usefulness as a sustained release preparation. As a method to improve this defect, the present inventors attempted to form an intermediate layer between the two as a kind of barrier to protect the release control mechanism of the sustained release portion. For this purpose, water-soluble polymer substances such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and methylcellulose, water-soluble substances such as lactose, mannitol, and sucrose, and hydrophilic substances such as starch and calcium hydrogen phosphate are used. Swelling substances such as crystalline cellulose and low-substituted hydroxypropyl cellulose, talc, magnesium stearate,
Substances with lubricant effect and adhesion prevention such as higher fatty acids and higher alcohols, sodium carbonate, hydrogen carbonate)
Combinations of additives with different properties, such as alkaline substances such as calcium carbonate, and each enteric coating substance are sequentially carried out.
We conducted a detailed study of the interactions. As a result, in most of these, residual insolubilized substances and delayed drug release were observed, and satisfactory results were not obtained.However, the combination of hydroxypropyl methyl cellulose acetate succinate and starch as an intermediate layer forming component was found. The present invention was completed by discovering that only one method is effective for interaction. The method of providing the intermediate layer is not particularly limited, but
Sustained release part granules 1 in centrifugal flow type coating granulator
1-100 parts by weight, preferably 5-100 parts by weight
A method of coating 50 parts by weight is preferred. If the amount is less than this, it is difficult to obtain a uniform intermediate layer, and therefore the release properties tend to vary, while if it is more than this, the disintegration of the intermediate layer forming component itself is affected, which is not preferable. Starch used in the intermediate layer is preferably used alone unless there is a special purpose, but it is possible to use small amounts in combination with other additives. The granules thus provided with the intermediate layer are coated with the enteric coating material hydroxypropyl methylcellulose acetate succinate. The coating amount is 1 to 50 parts by weight, preferably 5 to 50 parts by weight, based on 100 parts by weight of the sustained release part granules.
It is 20 parts by weight. If it is less than this, the acid resistance in the stomach will be insufficient, and if it is more than this, the dissolution at the pH in the upper part of the small intestine will be delayed, causing a problem in bioavailability. In addition, a plasticizer such as polyethylene glycol, propylene glycol, triethyl citrate, triacetin, glycerin, glycerin fatty acid ester, etc. can be added to the enteric coating material as necessary. The portion obtained through the steps above is the sustained release portion. Next, a mixed powder of cornstarch containing flavoxate hydrochloride, lactose, low-substituted hydroxypropylcellulose, crystalline cellulose, talc, etc. is coated thereon in the same manner as in the granulation of the sustained-release portion to form the sustained-release portion. Finally, in order to mask the bitter taste of flavoxate hydrochloride, polyvinyl acetal diethylamino acetate, which is an acid-soluble coating material, is coated. The coating amount is 1 to 30 parts by weight, preferably 1 to 15 parts by weight, per 100 parts by weight of the sustained release part granules. If it is less than this, sufficient masking will not be achieved and a bitter taste will occur in the mouth, and if it is more than this, it will be difficult to dissolve quickly under acidic conditions, and therefore initial medicinal efficacy may not be expected. Furthermore, considering that many of the subjects who take flavoxate hydrochloride preparations are elderly, acid-free symptoms cannot be underestimated. In that case, it was revealed that with the above-mentioned coating amount, the drug release properties of the immediate release portion were not significantly different from those of the JP No. 1 solution under acidic conditions even at around pH 6. Regarding the coating of polyvinyl acetal diethylamino acetate, a plasticizer such as polyethylene glycol, propylene glycol, triethyl citrate, triacetin, glycerin, glycerin fatty acid ester can be added as necessary. In the present invention, the blending ratio of flavoxate hydrochloride in the immediate release part and the sustained release part is 1=0.5 to 4, preferably 1:1 to 4, particularly preferably 1:2,3 in terms of weight ratio. If the blending ratio is less than 1:0.5, the blood concentration pattern will be almost the same as that of conventional products, so it will be difficult to achieve the sustainability objective of the present invention. With the release dose, the blood concentration does not increase at the initial stage of administration, and the duration can be extended.

【stomach. One of the features of the flavoxate hydrochloride sustained release laminated preparation of the present invention is that the immediate release portion and sustained release portion are integrated. It is a well-known fact that in a type of side ridge in which immediate release part granules and sustained release part granules are mixed and formed, the composition ratio of both granules in a dosage unit is difficult to be constant and varies widely. The reason for this is thought to be the mixing operation, which is caused by factors such as the specific gravity, size, surface condition, and chargeability of both granules.
In any case, variations in the composition ratio are a serious defect that impairs the reliability and usefulness of sustained-release preparations. The present inventors conducted a detailed study on flavoxate hydrochloride, and as a result, invented the layered sustained-release preparation of the present invention, which improves these defects. [Example] A more detailed explanation will be given below with reference to Examples, Comparative Examples, and Test Examples. Example 1 600 g of commercially available spherical granules (manufactured by Freund, trade name: Non-barrel, 14-2014-2O) were added to a centrifugal fluid coating granulator (70 made by India Ltd., trade name: CF).
-360) and hydroxypropyl cellulose (
While spraying a 5% solution of (hereinafter referred to as RPC), 560 g of flavoxate hydrochloride, 300 g of corn starch, 70 g of low-substituted hydroxypropyl cellulose, 1 talc 4
After gradually adding 0 g of the mixture and granulating it, corn starch 32 (Ig) was subsequently coated as an intermediate layer. After drying, 500 g was coated with a fluidized bed coating device (manufactured by Fuji Sangyo Co., Ltd.).
Product name: 5TRB8) and ethanol/containing 50 g of enteric coating material hydroxypropyl methyl cellulose acetate succinate (hereinafter referred to as AQO^T-M), log triethyl citrate, and 15 g of talc.
Aqueous mixed solution 1400- was sprayed to obtain sustained release part granules. Next, 555 g of sustained-release aB pellets were put into a centrifugal flow type coating granulator, and while spraying a 5% solution of NPC, a mixture of 0 g of Flavoxatoro hydrochloride, 45 g of corn starch, and 3 g of talc was gradually added to coat the immediate release portion. did. After drying, 500 g of the immediate release part coated granules were put into a fluidized bed coating device and 300 rn1 of an ethanol solution containing 15 g of polyvinyl acetal diethylaminoacetate (hereinafter referred to as "HeB"), 5 g of macrogol-60003, and 1.5 g of talc was sprayed. The flavoxate hydrochloride sustained release laminated preparation of the present invention was obtained. Comparative Example 1 After granulating the sustained release portion in the same manner as in Example 1, drying was performed without covering the intermediate layer. After drying, perform the same operation on 500g of granules to obtain 800A
Sustained release part granules coated with TM were obtained. Next, 500 g of the sustained release part granules were put into a centrifugal fluid coating granulator, and while spraying a 5% solution of IPC, a mixture of 65 g of flavoxer hydrochloride, 47 g of cornstarch, and 3 g of talc was gradually added to form the immediate release part. coated. After drying, 500 g of immediate-release part-coated granules were put into a fluidized bed coating device, and A [iA 15 g, macrogol-6
An ethanol solution containing 300 g of flavoxate hydrochloride and 1.5 g of talc was sprayed to obtain a sustained-release laminated preparation of flavoxate hydrochloride. Comparative Example 2 The same operation was carried out using hydroxypropyl methyl cellulose phthalate (hereinafter referred to as HP-55) in place of the enteric coating material AQOAT-M in Comparative Example 1.
A sustained-release laminated preparation of flavoxate hydrochloride was obtained. Comparative Example 3 In place of the enteric coating material AQOAT-M in Comparative Example 1, the same operation was carried out using methacrylic acid ethyl acrylate copolymer (hereinafter referred to as Eudragio L30 Rho 55), and a sustained release laminated preparation of flavoxate hydrochloride was prepared. I got it. Comparative Example 4 The same operation was carried out using methacrylic acid methyl methacrylate copolymer (hereinafter referred to as Eudragift L-100) instead of the enteric coating material AQOAT-M in Comparative Example 1, and a flavoxate hydrochloride sustained release laminate was obtained. A formulation was obtained. Comparative Example 5 Carboxymethylethyl cellulose (hereinafter referred to as CMB) was substituted for the enteric coating material AQO^T-M in Comparative Example 1.
A similar operation was performed using (referred to as C) to obtain a sustained-release laminated preparation of flavoxate hydrochloride. Comparative Example 6 As a comparative test of the components of the intermediate layer, instead of cornstarch, which is a component of the intermediate layer in Example 1, hydroxypropyl methyl cellulose was coated on the sustained release part granules in an amount of 0% by weight. A sustained-release laminated preparation of flavoxate hydrochloride was obtained. Comparative example? As a comparative test of the components of the intermediate layer, low-substituted hydroxypropyl cellulose was coated in an amount of 20% by weight on the sustained release part granules instead of cornstarch, which was a component of the intermediate layer in Example 1, and hydrochloric acid was added. A flavoxate sustained release laminated preparation was obtained. Comparative Example 8 As a comparative test of the components of the intermediate layer, lactose was coated in an amount of 20% by weight on the sustained release part granulated neck granules instead of cornstarch, which was a component of the intermediate layer in Example 1, and flavoxate hydrochloride was coated. A sustained release laminated preparation was obtained. Comparative Example 9 The same operation was carried out using IP-55 instead of the enteric coated material ^QO^TM in Example 1 to obtain a sustained-release laminate preparation of flavoxate hydrochloride. Comparative Example 10 As a comparative test of the components of the intermediate layer, instead of cornstarch, which is a component of the intermediate layer in Comparative Example 9, hydroxypropyl methylcellulose was coated on the sustained release part-formed rLM grains in an amount of 10% by weight, and flavoxate hydrochloride was coated. A sustained release laminated preparation was obtained. Comparative Example 11 As a comparative test of the components of the intermediate layer, low-substituted hydroxypropylcellulose was coated in an amount of 20% by weight on the sustained release part granules instead of cornstarch, which is a component of the intermediate layer in Comparative Example 9. A sustained-release laminated preparation of flavoxate hydrochloride was obtained. Comparative Example 12 As a comparative test of the components of the intermediate layer, lactose was coated in an amount of 20% by weight on the sustained release part granules instead of cornstarch, which was a component of the intermediate layer in Comparative Example 9. A release laminated formulation was obtained. Test Example 1 The granules obtained in Example 1 and Comparative Examples 1 to 5 were subjected to a dissolution test using the Japanese Pharmacopoeia No. 1 and No. 2 liquids. The test method was to test granules equivalent to 400 mg of hydrochloric acid flavoxate in the first liquid for 2 hours, then transfer the sample to the second liquid, and then conduct the test for 3 hours. Sampling was performed at each time, and the elution amount was determined by absorbance method. The liquid volume was 9QQd, and the paddle method (10 lrpm) was used.As shown in Figure 1, rapid release of all granules was observed in the first liquid, and 30% of the drug amount in the immediate release portion was However, the behavior of the second solution is quite different, and whereas MrL, which is coated with enteric coating material directly on the sustained release part, shows slow release.
A clear rapid release is observed for the corn starch coated granules containing the intermediate tL acid component. Table 1 shows the condition of the granules during the dissolution test. In the case of granules in which the sustained release part is directly coated with an enteric coating material, the situation in the second liquid differs depending on the coating, and the AQO
AT-M, CMIliC, tHydragift L-100
II is a type that remains as granules or fragments with some of the granules destroyed for a long time, whereas II
With P-551 Eudragift 300-55, the granules start to stick to each other a few minutes after being transferred to the second liquid! ! A situation was observed in which these adhered aggregates remained in suspension for a long time. Furthermore, Table 2 shows the elution test results for three cases of each enteric coating material. Naturally, large variations in release properties can be seen in the types that cause adhesion and aggregation. From the results of the above elution test, it was found that providing an intermediate layer is effective in solving the problem related to the insolubilization phenomenon between flavoxate hydrochloride and the enteric coating material. Table 2 Test Example 2 Example 1, Comparative Example 6.7.8.9.1 (1, 11, 12
A dissolution test was conducted on the granules obtained in the same manner as in Test Example 1, and the effects of the intermediate layer forming component and the enteric coating material were compared. As shown in Figures 2 and 3, in terms of drug release after transfer to the second liquid, granules using corn starch showed the fastest release, while granules using hydroxypropyl methylcellulose and low im Granules using propylcellulose and lactose showed a slight improvement compared to granules that did not coat the intermediate layer (see Figure 1), but insolubilized substances still remained due to the interaction between flavoxate hydrochloride and the enteric coating material. was observed, indicating slow drug release. Further, as is clear from the figure, it was found that hydroxypropyl methylcellulose acetate succinate was used as the enteric coating material. Based on these results, in order to improve the problems related to insolubilization of the coating material and drug release properties due to the interaction between flavoxate hydrochloride and the enteric coating material, it is necessary to create an intermediate layer containing starch as an essential component on the sustained release part. It has been found that the most effective method is to coat the film with hydroxypropyl methyl cellulose acetate succinate, which is an enteric coating material. Test Example 3 The flavoxate hydrochloride sustained release laminated preparation of the present invention obtained in Example 1 was administered to healthy adults according to the test conditions below, and 3-methylflavone-8-carboxylic acid, the main metabolite of flavoxate hydrochloride, was The urinary excretion amount of the drug was measured and the sustained-release formulation was evaluated. [Test conditions] Five healthy adult male subjects were tested during fasting (test start 1).
The urine was taken with 100ml of water under two conditions: 2 hours before (breakfast on the day of the test) and after a light meal, and urine was collected for up to 24 hours according to a preset urine collection schedule. Both tests were conducted after a one week or more period of physical therapy. The dosage was approximately 1.3 g of flavoxate hydrochloride sustained-release laminated preparation (containing 400 mg of flavoxate hydrochloride) once a day, and 1 tablet of Bradalon (manufactured by Nippon Shinyaku Co., Ltd., containing 20 On+g of flavoxate hydrochloride per tablet) as a control. was once a day. [Test Results] The test results are shown in Table 3 and FIG. 4, respectively. (See next page) Table 3 Parameters related to urinary excretion amount during human administration RT Dispersion of residence time in the body The sustained release laminated formulation of frapoxate hydrochloride of the present invention is accompanied by a decrease in bioavailability compared to the control tablet. However, there was a clear delay in the time to reach the maximum urinary excretion rate, which is an indicator for sustained-release preparations, and a significant prolongation of the average retention time (approximately 1.6 times in the fasting state and approximately 2 times in the non-fasting state). 2 times), and it can be said that it has sufficient utility as a sustained-release preparation. In addition, since the maximum urinary excretion rate is comparable to that of the normal dose (200 mg), the sustained-release laminated preparation of frapoxate hydrochloride of the present invention is also excellent in terms of safety in the body.

【Effect of the invention】

The flavoxate hydrochloride sustained-release laminated preparation of the present invention is designed to improve the problems associated with insolubilization of the coating material and drug release properties due to the interaction between flavoxate hydrochloride and the enteric coating material. By using hydroxypropyl methylcellulose acetate succinate, which is a coating material, as an essential component, stable drug release was ensured and the usefulness as a sustained release preparation was significantly increased. In addition, by integrating the sustained-release portion and sustained-release portion into a laminated type, it is possible to provide a preparation with a more stable drug composition ratio between the sustained-release portion and sustained-release portion than in the conventional mixed type. As a result of providing a masking layer made of an acid-soluble film material to improve the bitter taste, it was also possible to improve the compliance problem that this drug had when taking it. The sustained-release laminated preparation of flavoxate hydrochloride of the present invention is to be taken per adult at a dose of 0.5 to 3 g (400 mg as flavoxate hydrochloride) twice a day, in the morning and in the evening.

[Brief explanation of the drawing]

FIG. 1 shows the dissolution test results regarding the presence or absence of an intermediate layer of granules made of enteric coated materials obtained in Example 1 and Comparative Examples 1, 2, 3, 4 and 5. Figures 2 and 3 show the results of the dissolution test of the granules obtained in Example 11 Comparative Example 6.7.8.9.10.11.12 using different intermediate layer components. FIG. 4 shows 3-methylflavone-8-carboxylic acid urinary excretion rate curves after administration of Bradarone tablets, which are the formulation of the present invention and the conventional formulation, in Test Example 3.

Claims (2)

[Claims] (1) A sustained release portion consisting of the above (a) to (c) of (a) a flavoxate hydrochloride-containing layer, (b) an intermediate layer, and (c) an enteric coating material layer; (d) a flavoxate hydrochloride-containing layer; A sustained release multilayer preparation of flavoxate hydrochloride, characterized in that it is formed by laminating two parts: e) an acid-soluble film material layer and an immediate release part consisting of the above (d) and (e). (2) The flavoxate hydrochloride sustained release multilayer preparation according to claim 1, wherein the component of the intermediate layer (b) is starch, and the component of the enteric coating material layer (c) is hydroxypropyl methyl cellulose acetate succinate.