JPS6314724A - Prazosin preparation - Google Patents

Abstract

PURPOSE:To provide the titled preparation containing crystalline prazosin and an enteric base (excluding acrylic resin). CONSTITUTION:The objective prazosin preparation can be produced by mixing crystalline prazosin (e.g. hydrochloride: the crystal form of the compound may be alpha-, beta- or gamma-form, etc., or their mixture; preferably fine powder with an average particle diameter of <=100mu, especially <=30mu) and an enteric base (a pH- dependent polymeric substance capable or forming a film from an organic solvent, insoluble in water and soluble at >=4.5 pH: e.g. cellulose acetate phthalate, shellac, etc.) at a weight ratio of 1:(0.05-50) and, if necessary, further mixing with a nonionic surfactant, excipient, disintegrant, colorant, etc. The dissolution rate of prazosin from the preparation is high and the released prazosin can be easily absorbed through digestive tracts. Prazosin is active to circulatory system (dilates peripheral vessel, decreases peripheral flow resistance and lowers pressure level) and is useful as a remedy for hypertension.

Description

[Detailed description of the invention] The present invention relates to novel prazosin formulations.

Prazosin has an effect on the circulatory system, that is, it dilates peripheral blood vessels, reduces peripheral resistance, and lowers blood pressure, and is usually used as a hydrochloride salt for the treatment of hypertension. The therapeutic effect of drugs that act on the circulatory system is closely related to blood concentration, but prazosin hydrochloride aqueous solution (2 m9
/100mg) is said to be orally administered to humans, the maximum blood concentration (Cmax) is 21.1 ng/ml, and the time to reach the maximum blood concentration (Tmax) is 1.2 hours. Prazosin hydrochloride is a drug that is poorly soluble in water, and more than 101 volumes of water (20°C) are required to dissolve 1 g of crystals.

Japanese Patent Publication No. 4188/1988 describes the crystal forms of prazosin hydrochloride as α-form, β-form, heptad-form and anhydrous form with a water content of about 1.5% or less, and an aqueous form with a water content of 4% or more. and prazosine metalate hydrochloride have been shown to exist. Furthermore, among these crystal forms, it has been shown that only the α form, which has relatively high solubility, is used for regular tablets and injections, since other crystal forms have problems with solubility and the like. However, the α-isomer absorbs moisture over time and converts into a stable hydrate with low solubility, so the formulation has a problem in that good solubility is not maintained.

The present inventors conducted research to increase the solubility of prazosin and develop a formulation with improved bioavailability. As a result, the solubility of prazosin was improved by blending prazosin with a specific base. It was discovered that a good preparation could be obtained (patent application filed in 1983).
0-61965 and 60-65060). As a result of further research, it was surprisingly found that by blending crystalline prazosin, for example, as a hydrochloride salt, with a specific enteric base, the solubility was better than that of the alpha form of prazosin hydrochloride, regardless of the crystal form. It has been found that a formulation with excellent properties can be obtained.

The present invention is a prazosin formulation characterized by containing crystalline prazosin and an enteric base (excluding acrylic acid resin).

The features of the prazosin preparation of the present invention are that the elution rate of prazosin from the preparation is high, absorption from the gastrointestinal tract is good, the area under the one-hour blood concentration curve (AUC) is large, and the bioavailability is improved. There are many things.

Pragsin is preferably a hydrochloride, but may also be a salt or free base of an inorganic acid such as hydrobromic acid or hydriodic acid. When using prazosin hydrochloride, α-form, β-form, γ-form
It may be in any crystal form, such as a body, or it may be a mixture of two or more thereof. These have an average particle size of 100μ or less, especially 3
It is preferable to use it as a fine powder of 0μ or less.

Crystalline prazosin and amorphous prazosin have different X-ray diffraction patterns and thermal behavior. Therefore, the two can be distinguished by X-ray diffraction and thermal analysis.

Prazosin hydrochloride fine powder can be obtained by friction-pulverizing crystalline prazosin hydrochloride using a ball mill, jet mill, vibrating ball mill, rough crusher, or the like. When pulverizing, for example, calcium lactate, hydroxypropyl methylcellulose, microcrystalline cellulose, talc, etc. can be added to reduce adhesion and aggregation.

The enteric base used in the present invention is a pH-dependent polymeric substance that has the property of forming a film from an organic solvent and is insoluble in water but dissolves at pH 4.5 or higher, such as shellac, acetic acid, etc. Heptalulose phthalate, hydroxypropyl methylcellulose phthalate) (HPMCP, Shin-Etsu Chemical product), hydroxypropyl methylcellulose acetate succinate (HPMCAS, Shin-Etsu Chemical product),
Examples include carboxymethylethyl cellulose (CMFC, a product of Freund Sangyo Co., Ltd.).

When producing the formulation of the present invention, for example, an enteric base is added as a powder or solution to fine powder of prazosin hydrochloride and mixed. At this time, nonionic surfactants, excipients, disintegrants, coloring agents, flavoring agents, deodorants, etc. can be added as necessary. Mixing is carried out in a conventional manner using a mortar, type mixer, cone mixer, etc. Note that when prazosin and the enteric base are mixed and ground for a long time, the solubility of prazosin from the preparation increases and the blood concentration tends to be sustained.

The mixing ratio of Pragsin and enteric base is 1:0.05 by weight.
-5o, preferably i:o, 1-2o. If the blending ratio of the enteric base is lower than this, the interaction with prazosin will be weak, and the increase in solubility and bioavailability will not be sufficient. Further, even if the blending ratio is higher than this, no particular effect can be obtained and the amount used increases, which is economically disadvantageous.

The mixture thus obtained can be made into fine granules, granules, hard capsules, tablets, etc. by a conventional method as it is or by adding a binder, a disintegrant, a lubricant, etc.

Preferred excipients include, for example, lactose, sucrose, glucose, crystalline cellulose, starch, and the like. As the binder, hydroxyglobil cellulose, hydroxypropyl methyl cellulose, methyl cellulose, gum arabic, etc. are preferable. When producing fine granules and granules, it is preferable to add a binder in the form of a solution or powder and perform granulation.

Granulation methods include extrusion granulation, crushing granulation, and dry % formula.The preparation of the present invention has a rapid rise in blood concentration (with a large AUC) and can significantly improve bioavailability.

Parts in the examples below mean parts by weight.

Example 1 Prazosin hydrochloride (anhydrous) 1 part carboxymethylethylcellulose 10 parts lactose
81 parts crystalline cellulose
Six parts of the above ingredients were placed in a vertical granulator (Fuji Sangyo) to form a mixed powder. 40 parts of a 5% hydroxypropylcellulose aqueous solution was added to this powder, kneaded, granulated, and dried to obtain granules.

Example 2 Planone hydrochloride/(anhydrous) 1 part Tween 80 (], 25 parts lactose
86 parts crystalline cellulose 6 parts The above ingredients were added to Example 1.
A mixed powder was prepared in the same manner as above. 40 parts of a 5% hydroxyglobil methylcellulose aqueous solution was added to this powder, kneaded, granulated, and dried to obtain granules.

Example 6 Prazosin hydrochloride (anhydrous) 1 part lactose
86 parts Crystalline cellulose 6 parts The above ingredients were placed in a mixer to form a mixed powder.

To this powder was added 110 parts of hydroxyglobil methylcellulose phthalate dissolved in ethanol, kneaded, granulated, and dried to obtain granules.

Comparative example Prazosin hydrochloride (anhydrous) 1 part lactose
90 parts crystalline cellulose 4 parts carboxymethyl cellulose 3 parts 5% to the mixed powder of the above ingredients
40 parts of hydroxypropyl cellulose aqueous solution was added and kneaded, granulated using an extrusion granulator and then dried to obtain granules.

Test Example 1 A dissolution test was conducted using the formulation of the present invention, a comparative formulation, and prazosin hydrochloride crystals. The crystal used was a No. 2 capsule filled with 2 mg of α-form crystals with an average particle diameter of 20 μm or less. In addition, after sieving the granules obtained in Example 1.2.6 and the granules obtained in Comparative Example through a 32-mesh sieve, about 200 mg
A hard capsule containing 2 m9 of prazosin hydrochloride in each capsule was prepared by filling each capsule into No.
They were designated as B, C, and comparative preparation P.

The dissolution test was conducted according to diurnal cycle 10 "Dissolution test method, second method (rotating paddle method)". That is, 20 ml of diurnal second liquid in the container.
Add a sample equivalent to 0ml and 201n9 as hydrochloric acid plugsin, and stir at 200ml using a stirring blade while keeping it at 67°C.
The mixture was stirred at rpm, and the amount of prazosin hydrochloride eluted over time was determined by UV absorbance method. The results are shown in Table 1.

It is known that the elution from the preparations A, B, and C of the present invention is faster and the amount of elution is larger than that from the comparative preparation P and crystals.

Table 1 Test Example 2 Preparations A and B of the present invention and comparative preparation P were orally administered to pegle dogs weighing approximately 10 kg in an amount equivalent to 2 mg of pragsine hydrochloride per dog, and the plasma concentration (ng/ml) was determined by high-performance liquid chromatography. Required by law. The results are shown in Table 2. From this result, it is known that the human plasma concentration of pragsin when the present invention preparations A and B are administered increases more rapidly than that of the comparative preparation P, indicating a higher plasma concentration.

Table 2 Applicant: Toa Eiyo Co., Ltd. Agent: Patent attorney Tadashi Kobayashi (1 male)

Claims (1)

[Claims] A prazosin preparation characterized by containing crystalline prazosin and an enteric base (excluding acrylic acid resin).