PHARMACEUTICAL PREPARATION FOR PERCUTANEOUS ADMINISTRATION CONTAINING BUNAZOSIN OR ITS SALT

Abstract: A pharmaceutical composition comprises (a) a pharmacologically effective amount of bunazosin or a pharmacologically acceptable salt thereof and (b) a monoglyceride of a fatty acid having 8 to 12 carbon atoms and/or a lactic acid ester of an aliphatic alcohol having 12 to 18 carbon atoms and is improved in percutaneous administration.

Description: The present invention relates to a pharmaceutical preparation for percutaneous administration containing bunazosin or its salt, and more particularly to a pharmaceutical preparation for percutaneous administration containing bunazosin or its salt which exhibits excellent permeation into the skin. Bunazosin or its salt is a 6,7-dimethoxy-quinazoline derivative which exhibits a hypotensive activity through blocking of a sympathetic α-receptor and known as a therapeutic agent for essential hypertension and renal hypertension. At the present time, a bunazosin hydrochloride preparation is limited to oral administration. It is known that percutaneous administration is more advantageous than oral administration in that the drug is more effectively utilized in the body because it enables the first-pass effect in the liver to be avoided and in that a persistent effect can be obtained. In the case of the above-described drug, persistence of the drug effect is particularly desired. For this purpose, efficient percutaneous absorption of the drug should be first attained. The present inventors have made extensive and intensive studies with a view to enhancing the percutaneous absorption of bunazosin or its salt and have examined the possibility of obtaining a pharmaceutical preparation for percutaneous absorption with which a persistence of the hypotensive activity can be obtained. In order to prepare a pharmaceutical preparation for percutaneous absorption containing bunazosin or its salt, it is necessary to use a vehicle which can dissolve bunazosin or its salt to a suitable extent and which improve the permeation of bunazosin or its salt into the skin. The present inventors have made extensive and intensive studies with a view to finding these vehicles. The present inventors have found through their studies that a monoglyceride of a fatty acid having 8 to 12 carbon atoms or/and an ester of lactic acid with an aliphatic alcohol having 12 to 18 carbon atoms can dissolve bunazosin or its salt to a more suitable extent than conventional vehicles and remarkably improves the permeation of the bunazosin or its salt into the skin, and this has led to the completion of the present invention. The bunazosin hydrochloride is a compound represented by the following structural formula: A pharmaceutical composition which comprises (a) a pharmacologically effective amount of bunazosin or a pharmacologically acceptable salt thereof and (b) a monoglyceride of a fatty acid having 8 to 12 carbon atoms and/or a lactic acid ester of an aliphatic alcohol having 12 to 18 carbon atoms and is suitable for percutaneous administration. It is preferred that a weight ratio of (b) to (a) ranges from 0.1 to 200. Accordingly, the present invention provides a pharmaceutical preparation for percutaneous administration containing bunazosin or its salt which comprises bunazosin or its salt and a monoglyceride of a fatty acid having 8 to 12 carbon atoms or/and an ester of lactic acid ester with an alphatic alcohol having 12 to 18 carbon atoms incorporated therein. Examples of the monoglyceride of a fatty acid having 8 to 12 carbon atoms include glyceryl monocaprylate, glyceryl monocaproate, and glyceryl monolaurate, among which glyceryl monocaprylate is particularly preferred. Examples of the ester of lactic acid with an aliphatic alcohol having 12 to 18 carbon atoms include myristyl lactate, cetyl lactate, and lauryl lactate. It is suitable to incorporate the monoglyceride of a fatty acid having 8 to 12 carbon atoms or/and the ester of lactic acid with an aliphatic alcohol having 12 to 18 carbon atoms in a combined amount of from 0.1 to 200 parts by weight based on the amount of bunazosin or its salt. It is preferred that bunazosin or its salt be incorporated in the pharmaceutical preparation in an amount of 0.1 to 20% by weight and the monoglyceride of a fatty acid having 8 to 12 carbon atoms and/or the ester of lactic acid with an aliphatic alcohol having 12 to 18 carbon atoms be incorporated in the pharmaceutical preparation in a total amount of 1 to 20% by weight. It is possible to further improve the permeation of bunazosin or its salt through an increase in the pH value of the pharmaceutical preparation of the present invention wherein the monoglyceride of a fatty acid having 8 to 12 carbon atoms or/and the ester of lactic acid with an aliphatic alcohol having 12 to 18 carbon atoms are incorporated. There is no particular limitation to the form of the pharmaceutical preparation of the present invention, and the pharmaceutical preparation may be in the form of any of ointments, creams, patches, lotions, etc. All of the vehicle ingredients commonly used as pharmaceutical preparations for percutaneous administration may be used as ingredients in addition to the monoglyceride of a fatty acid having 8 to 12 carbon atoms or/and the ester of lactic acid with an aliphatic alcohol having 12 to 18 carbon atoms contained in the pharmaceutical preparation of the present invention, and any of oleaginous base ingredients and aqueous base ingredients may be used. Examples of the oleaginous base ingredients include white petrolatum, purified lanolin, squalane, silicone, liquid paraffin, vegetable oils, and waxes. Examples of the aqueous base ingredients include water, lower alcohols, polyhydric alcohols, and water-soluble polymers. Examples of the base ingredient, e.g., polymer compositions, which are commonly used for a patch include those having tackiness, such as natural rubbers, synthetic rubbers, styrene-isoprene-styrene block copolymers (SIS), polyacrylic ester resins and polyisobutylene resins; soft polyamide resins; polyvinyl alcohol; and polyacrylic resin. Besides the above-described components, the pharmaceutical preparation of the present invention may contain optional additives used in known pharmaceutical preparations for percutaneous administration, such as surfactants, stabilizers, preservatives, and antiseptics. The pharmaceutical preparation of the present invention has the following advantages. (1) The bioavailability is high because it is free from a first-pass effect in the liver. (2) It brings no gastro-intestinal disturbances. (3) Its action is persistent. (4) The administration can be immediately interrupted when adverse reactions (e.g., hypersensitive symptom such as eruption) are observed, so that high safety can be attained. (5) Since the rate of increase of the drug concentration in the blood is slower than in oral administration, it is possible to prevent vertigo and lightheadedness attributable to rapid blood pressure decrease. Brief Description of the Drawings: Figs. 1 to 4 are graphs, respectively showing the results of experiments on skin permeability with samples described in Experimental Examples 1 to 4. The present invention will now be described in more detail by way of Experimental Examples which demonstrate the effect of the monoglyceride of a fatty acid having 8 to 12 carbon atoms or/and the ester of lactic acid with an aliphatic alcohol having 12 to 18 carbon atoms on the permeation of bunazosin or its salt into the skin, and Examples of the present invention which should not be construed as limiting the scope of the present invention. Experimental Example 1 The following various test samples for use in experiments on skin permeation in vitro were prepared. The results are shown in Fig. 1. Preparation of test samples Sample 1 of the present invention: A propylene glycol solution containing 5% by weight of glycerin mono/dicaprylate (Homotex PT® which contains glycerin monocaprylate and glycerin dicaprylate in a weight ratio of 1 : 1; a product of Kao Corp.) was used as a base, and bunazosin hydrochloride was suspended in the base to prepare a sample (containing 200 mg of bunazosin hydrochloride in 2 g of the sample). Comparative Sample 1: Propylene glycol was used as a base, and bunazosin hydrochloride was suspended in the base (containing 200 mg of bunazosin hydrochloride in 2 g of the sample). Comparative Sample 2: 1,3-Butylene glycol was used as a base, and bunazosin hydrochloride was suspended in the base to prepare a sample (containing 200 mg of bunazosin hydrochloride in 2 g of the sample). Comparative Sample 3: Dipropylene glycol was used as a base, and bunazosin hydrochloride was suspended in the base to prepare a sample (containing 200 mg of bunazosin hydrochloride in 2 g of the sample). Method of experiment on skin penetration in vitro Abdominal hair of a male Wistar rat weighing about 230 g (8- to 9-week old) was removed under anesthesia. After 24 hr, the rat was similarly anesthetized to confirm that the skin was free from a wound. Then, the skin was wiped clear with 70% ethanol, followed by ablation of the entire skin of the abdomen. The ablated skin was fixed to the lid of a horizontal membrane type in-vitro diffusion cell having a permeation area of 7.54 cm² in such a manner that the skin side served as a donor surface. 50 ml of a phosphate buffer having a pH value of 7.4 was used as a receptor solution. 2 g of the sample solution was dropped and applied to the donor side. The lid was carefully fixed to the receptor so that no bubbles remained on the donor side, followed by incubation in an incubator at 32°C. The receptor solution was stirred with a stirrer and sampled in an amount of 0.5 ml at predetermined time intervals to quantitatively determine bunazosin hydrochloride. The quantitative determination was conducted by high-performance liquid chromatography. As can be seen from the results shown in Fig. 1, the 24 hr-cumulative skin penetration of bunazosin hydrochloride when a propylene glycol solution containing 5% by weight of glycerin mono/dicaprylate was used as the basic formulation was remarkably good as high as about 40 times to that obtained when propylene glycol, 1,3-butylene glycol, or dipropylene glycol was used as the basic ingredient. Experimental Example 2 The following test samples were prepared to conduct experiments on skin penetration in vitro in the same manner as that of Experimental Example 1. The results are shown in Fig. 2. Preparation of test samples Sample 2 of the present invention: A propylene glycol solution containing 5% by weight of cetyl lactate was used as a vehicle, and bunazosin hydrochloride was suspended in the vehicle to prepare a sample (containing 200 mg of bunazosin hydrochloride in 2 g of the sample; pH value: 3.9). Sample 3 of the present invention: A propylene glycol solution containing 5% by weight of cetyl lactate was used as a base, and bunazosin hydrochloride was suspended in the base to prepare a sample (containing 200 mg of bunazosin hydrochloride in 2 g of the sample). The pH of the sample was adjusted to 7 with a 1 N aqueous NaOH solution. Sample 4 of the present invention: A propylene glycol solution containing 5% by weight of cetyl lactate was used as a base, and bunazosin hydrochloride was suspended in the base to prepare a sample (containing 200 mg of bunazosin hydrochloride in 2 g of the sample). The pH of the sample was adjusted to 8 with a 1 N aqueous NaOH solution. Sample 5 of the present invention: A propylene glycol solution containing 5% by weight of cetyl lactate was used as a base, and bunazosin hydrochloride was suspended in the base to prepare a sample (containing 200 mg of bunazosin hydrochloride in 2 g of the sample). The pH of the sample was adjusted to 9 with a 1 N aqueous NaOH solution. Comparative Sample 4: A propylene glycol solution was used as a base, and bunazosin hydrochloride was suspended in the base to prepare a sample (containing 200 mg of bunazosin hydrochloride in 2 g of the sample; pH value: 3.9). As can be seen from the results shown in Fig. 2, the skin penetration of bunazosin hydrochloride when a solution containing cetyl lactate was used as the base ingredient was remarkably superior to that when only propylene glycol was used as the base ingredient. Further, in Fig. 2, the skin penetration was improved by an increase in the pH value of the sample of the present invention. Experimental Example 3 The following various test samples for use in experiments on skin penetration in vitro were prepared in the same manner as that of Experimental Example 1. The results are shown in Fig. 3. Preparation of test samples Sample 6 of the present invention: A propylene glycol dicaprylate solution containing 5% by weight of glycerin monocaprylate was used as a base, and bunazosin hydrochloride was suspended in the base to prepare a sample (containing 200 mg of bunazosin hydrochloride in 2 g of the sample). Sample 7 of the present invention: A propylene glycol dicaprylate solution containing 5% by weight of glycerin monocaprate was used as a base, and bunazosin hydrochloride was suspended in the base to prepare a sample (containing 200 mg of bunazosin hydrochloride in 2 g of the sample). Sample 8 of the present invention: A propylene glycol dicaprylate solution containing 5% by weight of glycerin monolaurate was used as a base, and bunazosin hydrochloride was suspended in the base to prepare a sample (containing 200 mg of bunazosin hydrochloride in 2 g of the sample). Comparative Sample 5: A propylene glycol dicaprylate was used as a base, and bunazosin hydrochloride was suspended in the base to prepare a sample (containing 200 mg of bunazosin hydrochloride in 2 g of the sample). As can be seen from the results shown in Fig. 3, the skin penetration of bunazosin hydrochloride when a propylene glycol dicaprylate solution containing a monoglyceride of an aliphatic acid having 8 to 12 carbon atoms was used as the base ingredient was remarkably better than when propylene glycol dicaprylate alone was used as the base ingredient. Experimental Example 4 The following various test samples for use to conduct experiments on skin penetration in vitro were prepared in the same manner as that of Experimental Example 1. The results are shown in Fig. 4. Preparation of test samples Sample 9 of the present invention: A propylene glycol solution containing 5% by weight of cetyl lactate was used as a base, and bunazosin hydrochloride was suspended in the base to prepare a sample (containing 200 mg of bunazosin hydrochloride in 2 g of the sample). Sample 10 of the present invention: A propylene glycol solution containing 5% by weight of myristyl lactate was used as a base, and bunazosin hydrochloride was suspended in the base to prepare a sample (containing 200 mg of bunazosin hydrochloride in 2 g of the sample). Sample 11 of the present invention: A propylene glycol solution containing 5% by weight of lauryl lactate was used as a base, and bunazosin hydrochloride was suspended in the base to prepare a sample (containing 200 mg of bunazosin hydrochloride in 2 g of the sample). Comparative Sample 6: Propylene glycol was used as a base, and bunazosin hydrochloride was suspended in the base to prepare a sample (containing 200 mg of bunazosin hydrochloride in 2 g of the sample). As can be seen from the results shown in Fig. 4, the skin penetration of bunazosin hydrochloride when a propylene glycol solution containing an ester of lactic acid with an aliphatic alcohol having 12 to 18 carbon atoms was used as the base ingredient was remarkably better than when propylene glycol alone was used as the base ingredient. Example 1 (oleaginous ointment) Glycerin mono/dicaprylate (Homotex PT®) was heated to 60°C and bunazosin hydrochloride was added thereto, followed by stirring to prepare a homogeneous mixture. Separately, sorbitan trioleate and white petrolatum were heated to 60°C and homogeneously mixed with each other. The above homogeneous mixture prepared by stirring the glycerin mono/dicaprylate and bunazosin hydrochloride was added and the resulting mixture was stirred to give a homogenous mixture. The mixture was allowed to cool at room temperature to yield an oleaginous ointment having the following composition: bunazosin hydrochloride 1.5% by weight glycerin mono/dicaprylate (Homotex PT®) 5 % by weight sorbitan trioleate 3 % by weight white petrolatum 90.5% by weight Example 2 (hydrophilic ointment) Glycerin monocaprylate, polyoxyethylene(20) sorbitan monooleate, macrogol ointment listed in the Pharmacopoeia of Japan, and a preservative were heated to 60°C and homogeneously mixed with each other. A finely divided powder of bunazosin hydrochloride was added and the product was sufficiently mixed, while cooling to yield a hydrophilic ointment having the following composition: bunazosin hydrochloride 2 % by weight glycerin monocaprylate 3 % by weight polyoxyethylene(20) sorbitan monooleate 2 % by weight macrogol ointment listed in the Pharmacopoeia of Japan 92.9% by weight preservative 0.1% by weight Example 3 (O/W type cream) Squalane, isopropyl myristate, stearic acid, glycerin monostearate, sorbitan monopalmitate, polyoxyethylene(20) sorbitan monostearate, and glycerin monocaprylate were heated together to 70°C to yield a homogeneous solution. Bunazosin hydrochloride was added to the resultant solution and stirred to prepare a homogeneous mixture. Propylene glycol, a preservative, and purified water heated to 60°C were gradually added thereto, and the mixture was allowed to cool to 30°C while stirring, thereby preparing an O/W type cream having the following composition: bunazosin hydrochloride 2 % by weight squalane 8 % by weight isopropyl myristate 4 % by weight stearic acid 4 % by weight glycerin monostearate 4 % by weight sorbitan monopalmitate 1.5% by weight polyoxyethylene(20) sorbitan monostearate 1.5% by weight glycerin monocaprylate 5 % by weight preservative 0.1% by weight purified water 64.9% by weight Example 4 (oleaginous ointment) Glycerin monolaurate and glycerin monocaprylate were heated to 55°C, and bunazosin hydrochloride was added to give a homogeneous mixture. This homogeneous mixture was added to a mixture of octyldodecyl myristate, sorbitan sesquioleate, purified lanolin, propylene glycol monostearate, and white petrolatum heated to 70°C to prepare a homogeneous mixture which was then allowed to cool while stirring, thereby preparing an oleaginous ointment having the following composition: bunazosin hydrochloride 1 % by weight glycerin monolaurate 3 % by weight glycerin monocaprylate 3 % by weight octyldodecyl myristate 10 % by weight sorbitan sesquioleate 5 % by weight purified lanolin 10 % by weight propylene glycol monostearate 2 % by weight white petrolatum 66 % by weight Example 5 (oleaginous ointment) Propylene glycol was heated to 60°C, and bunazosin hydrochloride was added and dissolved therein. A mixture of cetyl lactate with Plastibase (trademark of a product of Squibb Japan Inc.; a mixture of 95% by weight of liquid paraffin with 5% by weight of polyethylene having a molecular weight of 10,000 to 30,000) prepared by heating them together to 60°C was added to the resultant solution. The mixture was allowed to cool at room temperature while stirring, thereby preparing an oleaginous ointment having the following composition: bunazosin hydrochloride 5 % by weight cetyl lactate 10 % by weight propylene glycol 15 % by weight Plastibase 70 % by weight Example 6 (oleaginous ointment) Propylene glycol was heated to 70°C, and bunazosin hydrochloride, Homotex PT®, cetyl lactate, cetostearyl alcohol, stearic acid, and propylene glycol monostearate were added and dissolved therein. The resultant solution was added to Plastibase heated to 70°C, and kneaded and mixed. The mixture was allowed to cool while stirring to prepare an ointment having the following composition: bunazosin hydrochloride 10 % by weight glycerin mono/dicaprylate (Homotex PT®) 5 % by weight cetyl lactate 10 % by weight cetostearyl alcohol 3 % by weight stearic acid 3 % by weight propylene glycol monostearate 8 % by weight propylene glycol 25 % by weight Plastibase 36 % by weight Example 7 (patch) A solution prepared by heating a mixture of SIS rubber, Arkon P-100® (alicyclic petroleum resin) and liquid paraffin to 130°C was mixed with a solution prepared by heating bunazosin hydrochloride, Homotex PT®, cetyl lactate, glycerin monoolate, and dibutylhydroxytoluene together to 70°C. The mixture was extended on a suitable support to prepare a patch having the following composition: SIS rubber 35 % by weight Arkon P-100® 24 % by weight liquid paraffin 18 % by weight bunazosin hydrochloride 2 % by weight Homotex PT® 10 % by weight cetyl lactate 5 % by weight glycerin monooleate 5 % by weight dibutylhydroxytoluene 1 % by weight Example 8 (gel-form ointment) 1.5 parts by weight of Carbopol 940® (carboxyvinyl polymer; a product of Goodrich) was suspended in 15 parts by weight of propylene glycol containing ethylparaben and propylparaben each dissolved therein. A suitable amount of purified water was added to the suspension while stirring to prepare a homogeneous slurry. Separately, bunazosin hydrochloride, cetyl lactate, and Homotex PT® were added to 15 parts by weight of propylene glycol, and the mixture was heated to prepare a solution. The slurry prepared above was gradually added to this solution to prepare a homogeneous gel-form ointment having the following composition: bunazosin hydrochloride 5 % by weight cetyl lactate 5 % by weight Homotex PT® 5 % by weight Carbopol 940® 1.5 % by weight propylene glycol 30 % by weight ethylparaben 0.05% by weight propylparaben 0.15% by weight purified water a suitable amount in total 100.0

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A pharmaceutical composition which comprises (a) a pharmacologically effective amount of bunazosin or a pharmacologically acceptable salt thereof and (b) a monoglyceride of a fatty acid having 8 to 12 carbon atoms and/or a lactic acid ester of an aliphatic alcohol having 12 to 18 carbon atoms. The composition as claimed in Claim 1, in which a weight ratio of (b) to (a) ranges from 0.1 to 200. The composition as claimed in Claim 1, which comprises 0.1 to 20 percent by weight of (a) and 1 to 20 percent by weight of (b). The composition as claimed in Claim 1, in which the monoglyceride is glyceryl monocaprylate and the lactic acid ester is selected from the group consisting of myristyl lactate, cetyl lactate and lauryl lactate. The use of a monoglyceride of a fatty acid having 8-12 carbon atoms and/or a lactic acid ester of an aliphatic alcohol having 12-18 carbon atoms for the preparation of a medicament for percutaneous administration comprising a pharmacologically effective amount of bunazosin or a pharmacologically acceptable salt thereof. The use according to claim 5 wherein the weight ratio of the monoglyceride and/or the lactic acid ester to bunazosin or a pharmacologically acceptable salt thereof ranges from 0.1-200. The use according to claim 5 wherein the monoglyceride and/or the lactic acid ester is comprised by 1-20 weight % and the bunazosin or a pharmacologically acceptable salt thereof is comprised by 0.1-20 weight %. The use according to claim 5 wherein the monoglyceride is glyceride monocaprylate and the lactic acid ester is selected from the group consisting of myristyl lactate, cetyl lactate and lauryl lactate. Claims for the following Contracting State : ES A process for the preparation of a medicament for percutaneous administration which comprises formulating a pharmacologically effective amount of bunazosin or a pharmacologically acceptable salt thereof with a monoglyceride of a fatty acid having 8-12 carbon atoms and/or a lactic acid ester of an aliphatic alcohol having 12-18 carbon atoms. The process according to claim 1 wherein the weight ratio of the monoglyceride and/or the lactic acid ester to bunazosin or a pharmacologically acceptable salt thereof ranges from 0.1-200. The process according to claim 1 wherein the monoglyceride and/or the lactic acid ester is comprised by 1-20 weight % and the bunazosin or a pharmacologically acceptable salt thereof is comprised by 0.1-20 weight %. The process according to claim 1 wherein the monoglyceride is glyceride monocaprylate and the lactic acid ester is selected from the group consisting of myristyl lactate, cetyl lactate and lauryl lactate. The use of a monoglyceride of a fatty acid having 8-12 carbon atoms and/or a lactic acid ester of an aliphatic alcohol having 12-18 carbon atoms for the preparation of a medicament for percutaneous administration comprising a pharmacologically effective amount of bunazosin or a pharmacologically acceptable salt thereof. The use according to claim 5 wherein the weight ratio of the monoglyceride and/or the lactic acid ester to bunazosin or a pharmacologically acceptable salt thereof ranges from 0.1-200. The use according to claim 5 wherein the monoglyceride and/or the lactic acid ester is comprised by 1-20 weight % and the bunazosin or a pharmacologically acceptable salt thereof is comprised by 0.1-20 weight %. The use according to claim 5 wherein the monoglyceride is glyceride monocaprylate and the lactic acid ester is selected from the group consisting of myristyl lactate, cetyl lactate and lauryl lactate.

Inventors: ASAKAWA, HIDENORI, FUJIMORI, HIROYUKI, KASAI, MASAYOSHI, KAYANO, MASANORI, OSAWA, SHIGEMITSU, YOSHIDA, MITSUHIRO
Applicants: EISAI CO., LTD., SANSHO CO., LTD.
Application year: 1989
Main classification: A61K31
IPC codes: A61K47, A61K31, A61P9, A61K9