TW200302745A - Oral solid solution formulation of a poorly water-soluble active substance - Google Patents

Abstract

The present invention relates to an immediate release formulation with enhanced bio-availability comprising a solid homogeneous and thermostable solution of a poorly water-soluble biologically active substance, characterised in that said solid solution comprises: a) the active substance in an amount of between 10 and 50% of the total weight of the formulation, b) a non-ionic hydrophilic surfactant ingredient, which is in the liquid form between 15 DEG and 30 DEG C, in an amount of between 20% and 70% of the total weight of the formulation and c) a pharmaceutically acceptable organic polymer or mixture of polymers, which polymer or mixture of polymers is in a liquid form above 60 DEG C and in a solid form below 30 DEG C, in an amount of between 5% and 70% of the total weight of the formulation, and d) optionally comprises a disintegrating agent in an amount of between 1% and 10% of the total weight of the formulation. The invention further relates to active substances formulated into the above form and methods for producing the formulation.

Description

200302745 (1) Description of the invention (The description of the invention should state: the technical field, prior art, content, embodiments and drawings of the invention) C. The technical field to which the invention belongs 3 The present invention relates to an active substance with poor water solubility. Oral solid solution formulation. More specifically, the present invention relates to a solid solution formulation of an active substance with poor solubility, in which the bioavailability of the active substance is greatly improved. I: Prior art 3 Solid solution formulations, generally in capsule form, are known in the art. EP 00 822 describes pharmaceutical formulations in the form of hard capsules filled with a liquid excipient which contains the active substance and solidifies into a solid composition or thixotropic colloid. US 4,795,643 discloses a solid solution formulation for delayed release of an active substance. The delayed release is caused by the use of a specific polymer, such as an acrylate polymer or an etherified cellulose. Many active substances have very poor solubility in water. When these live substances are administered into the body, they often have poor bioavailability due to poor solubility in digestive juices. To solve this problem, several methods have been developed, such as micronization, inclusion in cyclodextrin, use of an inert water-soluble carrier, nanocrystals or amorphous using solid dispersions (w〇 嶋 ⑽) or active substances form. 2 The impact of the above methods on bioavailability often depends on the nature of the active substance. Moreover, the dosage forms developed to date have often been defective, such as poor thermodynamic stability, critical or difficult manufacturing processes, or poor batch-to-batch reproducibility. [Abstract] 200302745 The invention's purpose is to provide an oral formulation for an active substance with poor solubility. Compared with the active substance in a conventional formula, the present & formula can be significantly improved. Bioavailability of active substances. Another object of the present invention is to provide a formula which can be prepared using a general formula formula 5 and equipment, which does not require a large investment. The present invention can achieve the above-mentioned object through an oral immediate-release formula, which has improved bioavailability, a homogenous solution containing a bioactive substance that is soluble in water, and a thermodynamically stable solid solution. The solid solution contains: 10 active substances, the amount of which is up to 50% of the total weight of the formula,) a non-ionic hydrophilic surfactant component, which is a liquid evil between 15 and 30 c , Its amount is 20% of the total weight of the formula ~, c) pharmacologically acceptable organic polymer or polymer mixture, the polymer or polymer mixture is liquid above 6 crc, below 30 it is solid 15 'The amount is 5% to 70% of the total weight of the formula, and d) optionally contains a disintegrant, the amount is 1% to 10% of the total weight of the formula. The definitions given below are helpful in understanding certain terms used within the framework of the present invention. Immediately release at least 75% of the drug in a dissolved form within 90 minutes. Thermodynamic stability means that during storage for up to 5 years under ambient conditions, the product does not undergo significant physical or chemical changes that may affect the performance of the product. Poor water solubility means that the water solubility of the active substance is less than 1/1000. This 200302745 发明, description of the invention means that the definition includes substances classified as "very slightly soluble,,, insoluble in quality" and "insoluble," according to the Pharmacopoeia definition (USP 24 / NF19, page 10, 2000 January). The non-ionic hydrophilic surfactants of Zhuanxiong are those amphoteric substances, which are soluble in water (they have a high HLB value), have surface activity, and do not ionize in aqueous solution (H Auterh〇ff, w〇rterbuch der

Pharmazie, Wissenschafliche Verlagsgesellschaft GmbH, Stuttgart 1981, p. 192). The hlb value is a value on a scale of 0 to 20, which is assigned to each surfactant based on the relative properties of the hydrophilic and hydrophobic portions of the surfactant molecule. Oil-soluble surfactants have low HLW4, while water-soluble surfactants have higher HLB values. The HLB value is calculated as follows: HLB = 20 (1-M0 / M) where M, where the molecular weight of the molecule is the molecular weight of the hydrophobic portion of the molecule. In the formulation, the ratio between the active substance and the nonionic hydrophilic surfactant is 1: 0.75 to 1: S. Say, yang & ^ is 1 · 1.5 · 1 ~ 4, most preferably 1 · 3. The ratio of the non-ionic hydrophilic surfactant to the pharmaceutically acceptable polymer or polymer mixture is i:: 〇05, preferably 15 · 1 ~ 1 · 〇 · 1 'most preferably about 1: 0.7 5. The escaped nonionic hydrophilic surfactant component is preferably selected from polyethylene glycol sorbitan fatty acid esters (polysorbates) and non-hydrogenated polyethylene oxide castor oil derivatives,%, +, Shi at 彳 τ 玍 物 'the hydrophilicity of the surfactant-20 200302745 发明, description of the invention lipophilic balance (HLB) value of 14-16. Polyethylene glycol polyethoxy ethers are commercially available from ICI Inc. under the trademark Ding Ween®. For the present invention 'Tween® 40' Tween® 60 or Tween® 80 is preferred. The most preferred compound is Tween® 80. Non-hydrogenated polyethylene oxide castor oil derivatives are commercially available from BASF Corporation under the trademark Cremophor®. For the present invention, the most preferred compound is Cremophor® EL. In one embodiment, the pharmaceutically acceptable organic polymer or polymer mixture consists essentially of polyethylene glycol (PEG) or a mixture of polyethylene glycols 10. PEG is a polycondensate of ethylene oxide and is commercially available from Union Carbide Corporation under the trademark Carbowax®. Preferred PEGs are those with a molecular weight of 1,000 to 50,000 Daltons. More preferred is PEG having a molecular weight of 4000 to 10,000 Daltons. The most preferred PEG has a molecular weight of about 6000 Daltons. 15 In another embodiment of the present invention, the pharmaceutically acceptable organic polymer or polymer mixture is mainly composed of a polyvinyl ° pyrrolidone (PVP) or a mixture of polyvinylpyrrolidone, which can be obtained from BASF Commercially available under the trademark Ko 11 idon® with a molecular weight of approximately 2500 to 3,000,000 Daltons. 20 In yet another embodiment of the present invention, the pharmaceutically acceptable organic polymer or polymer mixture mainly consists of polyvinyl alcohol (PVA) or a polyvinyl alcohol mixture, and is commercially available from Shin-Etsu Chemical Co. Trademark Poval® with a molecular weight of approximately 30,000 to 200,000 Daltons. The formulation optionally contains a disintegrant, the amount of which is 1% of the total weight of the formulation 200302745 发明, the description of the invention ~ 10%. A disintegrant is usually not required, but in some cases, in order to increase the solubility of the formulation due to swelling and increase the water transported into the formulation when in contact with the / disintegrating medium, a small amount of such a Reagents may be advantageous. An example of a disintegrant is PrimOjel @, which is commercially available from Penwest 5 1 > 1 ^ 011 & (^ 11 Kayama. Other disintegrants that can be used are commercially available Ac-di-Sol®, Lidon C! L® commercially available from BASF or poiypiaS (jone) commercially available from ISP. A particularly preferred dosage form of the above formulation is a hard capsule, which is filled with a homogeneous melt mixture, The melt mixture is allowed to solidify in situ. Another method of preparing the composition is to fill the blaze mixture into a soft elastic capsule or form a molded tablet, such as the melt The mixture is filled into a tablet mold or the partially cured melt mixture is shaped into a tablet shape, which can be similarly accomplished by the melt extrusion process of Knoll AG, Ludwigshafen, 15 brd. It can be known that: the method of the present invention is repeated There is virtually no limitation on the active substance to be formulated. As has been pointed out above, the compounded active substance has poor solubility in water, and the present invention provides an improvement in the dissolution performance of the active substance, such that the active substance The human digestive tract becomes more soluble in a substantially aqueous 20 system. The active substance is usually used in an amount of about 0 ~ 50m%, preferably in an amount of! ~ 50wt%, more preferably in an amount of about 10 ~ 50% by weight 〇—The active substance with poor solubility in water and particularly suitable for the method of the present invention is a substance having the following general formula described in EP 0733642: 200302745 发明, description of the invention

(I) wherein: R] is selected from alkoxy (C) -c6) alkyl which may be substituted by alkoxy, wherein phenyl may be (Ci-c: 6) alkyl, (Cl-C6) alkoxy Or 5 halogen-substituted phenyl- (Ci-C6) -alkyl and phenoxy- (c) -c6) -alkyl, and naphthyl- (CVC6) -alkyl, R2 and R3 are independently hydrogen Or halogen, R4 is a group that forms a biolabile ester, M is a metal ion, preferably a divalent metal ion, and 10η is 1, 2 or 3. (Ci-C4) alkyl is defined as a linear or branched alkyl group containing 1 to 4 carbon atoms. (C) -C4) Alkoxy is defined as a straight-chain or branched alkoxy group containing 1 to 4 carbon atoms. The invention therefore also relates to a solid solution formulation of a compound of formula I having poor water solubility as defined above. M is preferably Li +, Mg2 +, Zn2 + or Ca2 + ions, most preferably Ca2 + ions, the heart is preferably phenethyl, R2 * r3 is preferably hydrogen, and R4 is preferably ethyl. A preferred compound is 3-[[[1- [2 · (ethoxycarbonyl) -4-benzylbutyl] cyclopentyl] carbonyl] amino] -2,3,4,5-tetrahydro-2-oxy Generation 1-11-1-benzazacycloheptatriene-calcium acetate. The most preferred compound is said compound in the form of 3S, 20 2 R. This compound is called compound S-Ca. Phase 10 200302745 玖, the acid described in the invention (3-[[[1- [2- (ethoxyquinyl) -4-phenylbutyl] cyclopentyl] weiyl] amino > 2,3,4 , 5-tetrahydro-2-oxo-11 ^ 1_benzoazacycloheptatriene_1_acetic acid) is called compound SH, and the corresponding s_cardiacylbenzylamine salt is called compound S-Mba. 5 The above formulas can be prepared using conventional formula procedures and equipment. Therefore, another aspect of the present invention is to provide a method for preparing the above-mentioned formulation, characterized in that a) combining the non-ionic hydrophilic surfactant component with the pharmaceutically acceptable organic polymer or polymer mixture Junyao is mixed at 50-70 ° C at 60-70 ° C, b) the active substance 10 is added to the sub-dissolution at the temperature, C) optionally, the resulting mixture is filled into capsules' And d) allow the resulting mixture to cure at room temperature. Alternatively, the non-ionic hydrophilic surfactant component, a pharmaceutically acceptable organic polymer or polymer mixture, and an active substance are mixed together and heated to 50 to 100 t, preferably 60 to 70 t Until a clear 15 solution is obtained, optionally, then the solution is filled into capsules. The following examples are intended to further illustrate the present invention in more detail, so these examples should not be considered as limiting the scope of the present invention in any way. I: Embodiment 3 Example 20 Example L Effect of Type and Amount of Surfactant on Release Preparation of the Formula The non-ionic hydrophilic surfactant Tween _c_phor EL and the hydrophilic polymer PEG6000 are heated above 60 ° c temperature. The active substance is added and dissolved in the body squeegee at the temperature. Fill the capsule with the size 0 (zero) with the obtained Luo liquid of 200320034545 and the invention description. The solution was cured in a capsule at room temperature. A larger amount of a surfactant is combined with a poorly water-soluble active substance and a hydrophilic polymer. The compositions are listed in Table 丨 for liquid-filled capsules, which contain 5011 1 § active substance. The effect of the type of surfactant neutralization on the release of the active substance from the liquid-filled capsule was determined.

Table 1 · Effects of the amount and type of surfactant on the solubility of the active substance (the amount is expressed in%) 10 Material composition,% ABCDEFG active substance *) 16.0 16.0 16.0 16.0 16.0 16.0 16.0 Tween 80® 0.0 12.0 24.0 48.0 nanana Cremophor EL ® 0.0 nanana 12.0 24.0 48.0 PEG 6000 84.0 72.0 60.0 36.0 72.0 60.0 36.0 ft? Gas group) 4-Phenylbutyl] cyclopentylyl] amino] -2,3,4,5 < Lice-2-milk Generation: 1H-, 1-% of this tick, miscellaneous peptone; calcium salt of small acetic acid (compound ^ to)-Not applicable na The dissolution test of the liquid-filled capsules was performed in an artificial gastrointestinal fluid at 37 ° C, using The USP II instrument uses a stirring speed of 100 rpm and uses a sinker per capsule. Starting from 400 ml of a medium with a pH of 2 prepared from 400 ml of 0.01 N hydrochloric acid, the pH of the medium was sequentially increased to test the solubility. After 1 hour of dissolution, remove 15ml of the medium and change the pH of the buffer to 4.5 by adding 88.5ml of 0.05N glacial acetic acid and 211.5ml of 0.05N sodium acetate solution. After 30 minutes, remove 5ml of medium 15 in vitro Dissolution test 1 solution system

12 200302745 发明, description of the invention, and adding 18_ ο · 2N_ hydrogen acid: sodium and potassium dichloride, i2Qmi, to change the pH of the buffer to 68. 2 5 hours later, remove 5ml of the medium to end Solubility test. Chromatography System 5 A UV-absorption detection system with a constant temperature oven and adjustable wavelength and integration system is used. The analysis column (length 3 cm, inner diameter 3 mm) is a C18-modified silica, and preferably a column with a particle size of 3 μm. The mobile phase consisted of a degassed mixture containing 350 ml of ammonium acetate and 800 μ trifluoroacetic acid in 350 ml of water and 650 ml of acetonitrile. The flow rate is 10.5 per minute. The column temperature was 40 ° C. The injection volume was the wavelength of the uv-absorption detector at 236 nm. For external standardization, 012 mg of compound s_Mba RS was dissolved in 1 ml of mobile phase. The dissolved amount of the compound S_H, expressed as a percentage relative to the label claim, is given by the following equation i:

% Dissolution = Isa xmst > < VsaxCx0.8152 IstxVstxLC 15 Equation 1 Calculation of the dissolved amount of compound S-Η Where: Ist = peak area of compound S-Η in the standard chromatogram;

Isa-Peak area of compound S-Η in the sample chromatogram; vst = dilution volume of the standard solution, expressed in ml (50ml); 20 = dilution volume of the sample solution, expressed in ml (400, 700, and 1000ml) mst = weight of compound S-MbaRS, in mg; C = purity of compound S-MbaRS, in% m / m; 200302745 发明, description of the invention

LC = declared amount of the label of the analyzed capsule, expressed as compound S-H; 0.8152 = ratio of compound S-fluorene to the molecular weight of the compound. 5 The dissolution results of formulas A, B, C, and D (see Table 1) containing Tween 80 as a surfactant determined by the above HPLC method are shown in Figure j (♦ = 0% '_ = 12%, 1 = 24%, repair = 48% of Tween 80). The dissolution results of formula E, j ^ G (see Table 丨) containing Cremophor EL as a surfactant are given in Figure 2 (♦ = 0%, _ < 2%, ▲ = 24%, spring 10 = 48% Cremophor EL) The results given in Figures 1 and 2 clearly show that the release of the active substance from the liquid-filled capsules is determined by the amount of hydrophilic surfactant used in the composition. The amount of active substance released increased with the increase of the surfactant dose. 15 More specifically, it can be seen that the release of the active substance at pH 2 (release data during the first 60 minutes of the dissolution test) is determined by the amount of surfactant in the composition. The pH changed from 2 to 4.5 (release data over the next 30 minutes), improving the release of the active substance from a composition containing a low level of a hydrophilic surfactant. At the end of the time period with a pH value of 4.5, it can be observed that when the composition contains at least 12% of the surfactant Cremophor EL or 24% of Tween 80, the active substance is completely dissolved by 70 . Finally, the pH change from 4.5 to 6.8 no longer affects the release data. When at least 12% Cremophor EL or 24% Tween 80 is used, the active substance remains completely dissolved. 14 200302745 (ii) Description of the invention Example 2. Effect of type of hydrophilic polymer on release The hydrophilic polymer in a liquid-filled capsule may be a polyethylene glycol product. The composition shown in Table 2 was used to test the effect of the molecular weight of the polymer on solubility. The formulation was prepared as described in Example 1. 5 Table 2. Material composition of composition containing different types of polyethylene glycol (%) D Η J Active substance * 16 16 16 Tween 80 48 48 48 PEG 4000 na 36 na PEG 6000 36 nana PEG 50000 nana 36 * Compound S -Ca; na = Not applicable. The solubility test was performed as described in Example 1. The dissolution results of the composition containing Tween 80 and different types of polyethylene glycols are given in Figure 3 (♦ = PEG 4000, diPEG 6000, hPEG 50000). It can be clearly seen that the release of the active substance from a composition containing PEG 4000 and PEG 50000 is comparable, but delayed compared to PEG 6000, but still not a sustained release formulation. The most preferred hydrophilic polymer is PEG 6000 because PEG 4000 will leak faster from the capsule due to its lower melting point. On the other hand, because PEG 50000 has a relatively high viscosity in the molten phase, this material is difficult to handle. Capsule formulations containing Cremophor EL as a surfactant have also demonstrated the effect of hydrophilic polymer types. An equivalent amount of Cremophor EL was used in place of the surfactants Tween 80 of compositions D, VII and J of the previous example. The dissolution test was performed as described in 200302745 (1) and the description of the invention. The dissolution results of the liquid-filled colloid containing 48% w_p ⑹ iridium are shown in Fig. 4 (、, =, PEG 600, 5000). Figure 4 clearly shows that the release of the actives from the liquid-filled 5 capsules with the hydrophilic polymers PEG 4000 and pEG 50000 is comparable, but delayed compared to PEG 6000. However, the formulation cannot be considered a sustained release formulation. Example 3. Effect of different cations on the release of the active substance. Several other metal ions such as Mg2 +, Na + and u + were used to replace the most preferred Ca2 + ion in the active substance shell formula. These active substances are formulated according to Composition D in Table i 10. This means that the formulation contains 6% active material, 48% Tween 80 and 36% PEG 6000. The formulation was prepared according to the method described in Example 1. Contains Ca2 +, Mg2 +,

The dissolution results of Na + or Li + active materials are shown in Figure 5 (❿ = ca2 +, ◊ = Mg2 + '□ =: Na +, △ = Li +). It can be seen from the dissolution result that the cation does not affect the release of the active substance. The curves are comparable at pH 2, pH 4.5 and pH 6.8. Example 4. Bioavailability study A cross study was conducted in 15 male subjects to test the bioavailability of liquid-filled hard capsules. Compound ^ (^ (Formula ΗσΙΙΙ) or compound S-Η (Formula Π) was used as a drug substance. The following formula was administered to the subject: ⑴ Liquid filled in a hard capsule 2x l03.7mg of compound S-Ca ( (Equivalent to 100 mg of compound SH), prepared according to Example 1 using composition D, (π) 2X 100 mg of compound SH in a hard capsule, a 25% m / m powder mixture with tricalcium phosphate, (III ) 8 16 200302745 发明, Description of invention X 25mg simple tablet, containing 25.94mg of compound S-Ca (equivalent to 25mg of compound SH), 172mg of microcrystalline cellulose PH101, 172mg of mannitol 25, 8mg of hydroxypropylmethyl fiber E5, 20 mg sodium starch glycolate and 2 mg § sodium monooctadecanol monosodium ester. The results given in Table 3 were obtained from the average plasma concentration 5 ′ shown in FIG. 6. Results from cross-study studies in male subjects Formula C maximum relative bioavailability I 2.7 1.8 II 1 1 III 1.9 1.5

The results in Table 3 indicate that the bioavailability of the drug substance from a liquid-filled hard capsule containing 103.7 mg of the compound S-Ca, 311 mg of Tween 80 and 234 mg of polyethylene glycol 6000 is higher than that in which the compound S_H is absorbed in the three dance phosphate The bioavailability of Formulation II, which is a 25% m / m powder mixture, is increased by 80%, which is 200 / 〇 higher than that of the simple tablet of compound ^^. [Schematic description]

Figure 1 shows the dissolution of compositions A, B, C and D in Table 1. Figure 2 shows the dissolution of compositions A, E, p and G in Table 1. Figure 3 shows the effect of polyethylene glycol type on active substance release. Figure 4 shows the effect of polyethylene glycol type on active substance release. Figure 5 shows the effect of different cations on the release of active substances. Figure 6 is the average plasma concentration of a cross study with compound s. [Representation of the main components of the diagram] (None) 17

Claims (1)

200302745 fe, a patent-pending fan-improved oral immediate release formulation with improved bioavailability, containing a homogeneous bioactive substance with poor water solubility, and a thermodynamically stable solid solution, characterized in that the solid solution contains ... a) 'Tangular substances, the amount of which is up to 50% of the total weight of the formula, b) non-ionic hydrophilic surfactant component, which is liquid between ι5 ^ ~ 30 ° C, and the amount is equal to the total weight of the formula Fiber ~ 70%, C) Pharmacologically acceptable organic polymer or polymer mixture, 50% polymer or polymer mixture at 6 (rc above is liquid, below 30 it is solid evil, the amount is formula 5% to 5% of the total weight, and d) optionally include a disintegrant in an amount of 5% to 10% of the total weight of the formulation. 2. 15 3. If the scope of patent application is the first! The oral immediate release formulation according to item 2, characterized in that the ratio between the active substance and the nonionic hydrophilic surfactant component is! : 0.75 ^: 5, and the ratio of surfactant to pharmaceutically acceptable polymer or polymer mixture is! : 4 ~ i: 〇. The oral immediate release formulation according to item 2 of the scope of the patent application, characterized in that the ratio of the surfactant to the pharmaceutically acceptable polymer or polymer mixture is 1 ·· 1.5 ~ 1: 01. 4. The immediate release formulation as described in item ⑴ of the patent application scope, wherein the non-ionic hydrophilic surfactant component is selected from polyethylene glycol sorbitan fatty acid esters (polyethoxy ethers) And the non-hydrogenated polyethylene oxide sesame seed oil derivative 'said non-ionic hydrophilic surfactant has a hydrophilic-lipophilic balance (HLB) value of 14-16. 5. According to the scope of the patent application: [immediate release formulation described in 4 to 4, its special 18 200302745, the scope of the patent application lies in 'The pharmaceutically acceptable organic polymer is polyethylene glycol or polyethylene glycol. Alcohol mixtures, wherein the molecular weight of each polyethylene glycol is from _ to 50,000 Daltons, preferably from 4,000 to 10,000 Daltons. 6. The immediate-release formulation according to items 1 to 4 of the scope of patent application, wherein the pharmaceutically acceptable organic polymer is polyvinylpyrrolidone or polyvinyl with a molecular weight of 2500 to 3000000 Daltons A mixture of pyrrolidone, or a mixture of polyethylene glycol or polyethylene glycol having a molecular weight of 3,000 to 20,000 Daltons. 7. The immediate release formulation according to items 1 to 6 of the scope of patent application, characterized in that the active substance with poor water solubility is a compound of the following general formula: Wherein: R] is selected from (C ^ CJ alkoxy (crc: 6) alkyl) which may be substituted by (CKC6) alkoxy, and its phenyl group may be (Ci-C6) alkyl, (c "C6) Roxy or halogen-substituted phenyl- (cvc) alkyl and phenoxy- (CrC6) _alkenyl 'and naphthyl- (CVC6) -alkenyl, R2 and R3 are independently hydrogen or! I, R4 is a group that forms a biologically unstable S, M is a metal ion, preferably a divalent metal ion, 19 20 200302745, the scope of patent application η is 1, 2 or 3 ° 8. As described in item 7 of the scope of patent application The above-mentioned immediate-release formulation, wherein ^^ is calcium in the form of 2 + ions. 9. The immediate-release formulation according to items 1 to 8 of the patent application scope, which is characterized by 'the poorly water-soluble active substance is 3 -[[[1- [2- (ethoxyquinyl) -4-phenylbutyl] cyclopentyl] carbonyl] amino] -2,3,4,5-tetrahydro_2_oxo-1Η- Calcium salt of 1-benzoazacycloheptatriene ---- acetic acid, preferably in the form of 3S, 2'R. 10. Formulation according to item 1 to 9 of the scope of patent application, contained in hard capsule 10 or In soft capsules. 11. Preparation of the formulation as described in claims 1 to 10 of the scope of patent application. Method, characterized in that a) mixing the non-ionic hydrophilic surfactant component with the π-physically acceptable organic polymer or polymer mixture at ~ 100C, and b) The active substance is added and dissolved at a temperature of 15 ° C, c) optionally, the resulting mixture is filled into capsules, and d) the resulting mixture is allowed to solidify at room temperature. The method for preparing a formulation according to the item, specifically, a) combines the non-ionic hydrophilic surfactant component with the pharmacologically acceptable organic polymer or polymer mixture and: 20 sexual substances Mix at 50-100. 0, b) optionally, fill the resulting mixture into capsules, and e) allow the resulting mixture to cure at room temperature. 20