CN1686143A - Hendecanoic acid testosterone self emulsified soft capsule composition and its preparation method - Google Patents

Abstract

The invention provides a testosterone undecanoate self-emulsifying soft capsule composition and a preparation method. The mass ratio of each component is: testosterone undecanoate is 0.1-20%, the oil phase is 7-80%, and the emulsifier is 17%. -90%. Dissolve testosterone undecanoate in the oil phase, mix emulsifiers in proportion to form a uniform solution, and pack into soft capsules. After oral administration, it mixes with the water in gastric juice, and spontaneously forms an emulsion under gastric peristalsis. The particle size of the emulsion droplet is below 5 μm, which can greatly improve the absorption speed and extent of the drug, thereby improving the bioavailability and curative effect of the drug. The testosterone undecanoate self-emulsifying soft capsule composition provided by the invention does not contain co-emulsifiers, can overcome the disadvantage of drug precipitation caused by alcohol components migrating into the gelatin capsule shell, and increase the stability of the composition. The testosterone undecanoate self-emulsifying soft capsule preparation of the invention has simple preparation process, low cost, stable performance, and is convenient for storage and transportation.

Description

Testosterone undecanoate self-emulsifying soft capsule composition and preparation method

technical field

The invention belongs to the field of pharmacy and relates to an oral soft capsule preparation and a preparation method, in particular to a self-emulsifying soft capsule composition of testosterone undecanoate and a preparation method.

Background technique

Testosterone undecanoate (TU) is a derivative of testosterone. It has strong androgenic and assimilative effects. Androgen can significantly promote protein synthesis (assimilation) and reduce amino acid decomposition (dissimilation), so that muscle growth and weight gain can be achieved. In addition, it also has the effect of enhancing bone marrow hematopoietic function. At present, the main dosage forms are injections and soft capsules, which are clinically used for male sexual dysfunction and infertility, male sexual dysfunction with abnormal sex chromosomes (Kranfield syndrome), and aplastic anemia. Testosterone undecanoate is very soluble in chloroform or benzene, soluble in ethanol, slightly soluble in vegetable oil, and insoluble in water. Due to the poor water solubility of the drug, it cannot be uniformly dispersed in water, so oral administration cannot be well absorbed through the gastrointestinal tract. At present, there are soft capsules of oral TU in the market, but it is reported that only 2% of the oral TU enters the blood circulation through the lymphatic system after metabolism in the body, and the bioavailability is low.

In 1992, Charman reported the self-emulsifying drug delivery system (Self-Emulsifying Drug Deliver System, SEDDS) on Pharm.Res. The system uses the oil phase as the carrier of hydrophobic drugs. Mix, adding co-emulsifier if necessary, to form a homogeneous, clear solution. The solution has good stability. Once it is mixed with the water phase, it can spontaneously form an oil-in-water emulsion at ambient temperature (usually 37°C body temperature) with only mild stirring, and the particle size is generally below 5 μm. In this homogeneous solution, the hydrophobic drug is dissolved in the oil phase, mixed with the water phase in gastric juice after oral administration, and spontaneously forms an emulsion under gastric peristalsis, and the drug is dispersed in small oil-in-water droplets and quickly dispersed in the gastrointestinal tract And be absorbed, thereby improving the bioavailability of the drug. Because the emulsification process of the solution is carried out automatically in the stomach, it is called self-emulsifying drug delivery system (SEDDS). With the increase of the amount of emulsifier, the particle size of the emulsion drops is further reduced, and a transparent or translucent microemulsion can be formed. There are relatively few oral self-emulsifying and self-microemulsifying products, but the success of the NeoralTM microemulsion concentrated soft capsules of cyclosporine A in 1994 made the self-emulsifying drug delivery system (SEDDS) and the self-microemulsifying drug delivery system (SMEDDS) ) as a drug carrier has attracted more and more attention. As a new drug delivery system that can improve the bioavailability of hydrophobic drugs, SEDDS has broad development prospects.

SEDDS is usually designed as a single-dose capsule. Generally speaking, solid SEDDS can have a larger drug content, but it is difficult to determine the state of the drug in solid SEDDS, so a self-emulsifying system in the form of a homogeneous liquid is generally used. The key to preparing this self-emulsifying drug delivery system is to optimize the type and ratio of the oil phase and emulsifier in the system, and to screen out a uniform composition with strong self-emulsifying ability. The oil phase required by SEDDS should be able to dissolve the prescribed amount of drug in a small amount. Even under low temperature storage conditions, there will be no drug precipitation, and it is easy to be emulsified by the emulsifier in the prescription. The oil phase includes vegetable oil, fatty acid, three Glycerides etc. At present, long-chain and medium-chain triglycerides with different degrees of saturation are commonly used to design self-emulsifying dosage forms. The emulsifier generally uses a nonionic surfactant with a high HLB value. The strong hydrophilicity of the emulsifier with a high HLB value is necessary for the immediate formation of oil-in-water emulsion droplets and the diffusion of the self-emulsion in a water-soluble environment. Different kinds of polyoxyethylene oleate and polyoxyethylene sorbitan are the most commonly used emulsifiers, with a general content of 30%-60%. Sometimes only the emulsifier can not quickly emulsify the solution, so it is necessary to add a co-emulsifier, generally a long-chain alcohol, ethylene glycol, propylene glycol, polyglycerin derivatives, such as ethanol, isopropanol, glycerin, polyethylene glycol, etc. glycol etc. In SEDDS soft capsules containing co-emulsifiers, alcohol and other volatile co-emulsifiers can migrate into the gelatin capsule shell, which may lead to the precipitation of fat-soluble drugs, thereby affecting the efficacy of drugs.

Self-emulsifying systems usually use self-emulsifying efficiency to evaluate their quality. It mainly includes the self-emulsification rate and the particle size of emulsion droplets after emulsification is complete. It is generally believed that the particle size of emulsion droplets is the main factor, which directly affects the absorption of drugs. Studies of two crude emulsion formulations of cyclosporin A showed that the smaller the emulsion droplets, the better the drug absorption. Increased bioavailability. A suitable self-emulsifying formulation can be optimized through the phase diagram.

At present, SEDDS has been used in various drugs, such as local anesthetics (lidocaine); antibiotics (norfloxacin); hormones (progesterone); immunosuppressants (cyclosporine); vitamins (VA, VE); Classes and insulin, somatostatin, calcitonin, etc. So far there is no report about the preparation of testosterone undecanoate into a self-emulsifying drug delivery system.

Contents of the invention

One object of the present invention is to provide testosterone undecanoate self-emulsifying soft capsule composition, the mass ratio that each component accounts for is: testosterone undecanoate is 0.1-20%, oily phase is 7-80%, emulsifier is 17-90%.

The used oil phase of the testosterone undecanoate self-emulsifying soft capsule composition provided by the invention includes vegetable oil, medium and long-chain triglycerides (containing 8-10 C), and the emulsifier used is a nonionic surfactant, including polysorbate Ester-80, polysorbate-85, polysorbate-20, polyoxyethylene hydrogenated castor oil, are generally mixed emulsifiers. The emulsifier used in the present invention is not limited to the above examples.

The mass ratio of the two emulsifiers in the mixed emulsifier is 1:0.3-5, and the mass ratio of the oil phase to the emulsifier is 1:0.25-10.

Another object of the present invention is to provide the preparation method of testosterone undecanoate self-emulsifying soft capsule composition: testosterone undecanoate is dissolved in the oil phase, and emulsifier is mixed in proportion to form a uniform solution, which is a self-emulsifying system. This system does not contain co-emulsifiers, which can overcome the shortcomings of alcohol components moving into the gelatin capsule shell and cause drug precipitation, and increase the stability of the composition. Take this solution and mix it with 0.1M hydrochloric acid solution, and it can be finished by gentle stirring. An oil-in-water emulsion is formed, and the particle size of the emulsion droplet is below 5 μm, and it is packed into a soft capsule. After oral administration, the emulsion is mixed with water in the gastric juice, and the emulsion can be formed spontaneously under the peristalsis of the stomach.

Different from the release mechanism of commercially available testosterone undecanoate soft capsules (without surfactant), the soft capsule composition provided by the present invention, after the capsule shell dissolves, the medicinal liquid is mixed with the water in the gastric juice, and the peristalsis of the stomach Emulsions are spontaneously formed under the environment, and the particle size of the emulsion droplets is 5 μm, which can even reach the nanometer level, which can greatly improve the absorption speed and degree of drugs, thereby improving bioavailability and curative effect. The testosterone undecanoate self-emulsifying soft capsule composition provided by the invention does not contain co-emulsifiers, can overcome the disadvantage of drug precipitation caused by alcohol components migrating into the gelatin capsule shell, and increase the stability of the composition. The testosterone undecanoate self-emulsifying soft capsule preparation of the invention has simple preparation process, low cost, stable performance, and is convenient for storage and transportation. After oral administration, it is automatically emulsified in the stomach, thereby improving bioavailability and efficacy.

Detailed ways

The present invention will be further described below in conjunction with specific examples, and these examples are for illustration purposes only, and are not intended to limit the scope of the present invention.

Example 1

A kind of mass percentage (%) of testosterone undecanoate self-emulsifying soft capsule composition

                                                           

                                                         

                                                                         

                                                                 

Preparation: Dissolve testosterone undecanoate in glyceryl caprylate, add polysorbate-80 and polysorbate-20 to form a uniform solution, mix the solution with 20ml 37℃ 0.1mol/L hydrochloric acid, and gently use a glass rod Stir to obtain a translucent emulsion with blue opalescence, with a particle size of about 3 μm.

Example 2

Another mass percentage (%) of testosterone undecanoate self-emulsifying soft capsule composition

                                                                           

                                                             

                                                           

                                               

Preparation: Dissolve testosterone undecanoate in glyceryl caprate, add polysorbate-80 and polysorbate-20 to form a uniform solution, mix the solution with 20ml 37℃ 0.1mol/L hydrochloric acid, and gently use a glass rod Stir to obtain a translucent emulsion with blue opalescence, with a particle size of about 3 μm.

Example 3

The third mass percentage (%) of testosterone undecanoate self-emulsifying soft capsule composition

                                                           

                                                                 

                                                     

                                           

Preparation: Dissolve testosterone undecanoate in vegetable oil, add polysorbate-85 and polysorbate-20 to form a uniform solution, mix the solution with 20ml 0.1mol/L hydrochloric acid at 37°C, and gently stir with a glass rod to obtain Blue opalescent transparent emulsion, most of the particle size is below 2μm.

Example 4: Component Mass Percentage (%)

                                          

                                                           

                                                                   

                                                                 

Preparation: Dissolve testosterone undecanoate in vegetable oil, add polysorbate-85 and polysorbate-20 to form a uniform solution, mix the solution with 20ml 0.1mol/L hydrochloric acid at 37°C, and gently stir with a glass rod to obtain Blue opalescent transparent emulsion, most of the particle size is around 3μm.

Example 5: Components Mass percentage (%)

                                                                         

                                                         

Polyoxy ethylene hydrogenation sesame oil 7.0

Jushan pearl ester-85 21.0

Preparation: Dissolve testosterone undecanoate in glyceryl caprylate, add polyoxyethylene hydrogenated castor oil and polysorbate-85 to form a uniform solution, mix the solution with 20ml 37℃ 0.1mol/L hydrochloric acid, and use a glass rod Stir gently to obtain a translucent emulsion with blue opalescence, with a particle size of about 3 μm.

Example 6: Components Mass percentage (%)

                                                             

                                                           

Polyoxy ethylene hydrogenated sesame oil 5.0

                                                                     

Preparation: Dissolve testosterone undecanoate in caprylic acid glyceride, add polyoxyethylene hydrogenated castor oil and polysorbate-85 to form a uniform drug solution, and mix the drug solution with 20ml of 0.1mol/L hydrochloric acid solution at 37°C , Stir gently with a glass rod to obtain a translucent emulsion with blue opalescence. The particle size is 2-10μm, mostly around 5μm.

Example 7: Components Mass percentage (%)

                                              6.0

                                                           

Polyte oxygenyl hydrogenated sesame oil 33.0

Jushan pearl ester-85 28.0

Preparation: Dissolve testosterone undecanoate in glyceryl caprylate, add polyoxyethylene hydrogenated castor oil and polysorbate-85 to form a uniform solution, mix the solution with 20ml 37℃ 0.1mol/L hydrochloric acid, and use a glass rod Stir gently to obtain a white emulsion with a particle size of about 5 μm.

Example 8: Components Mass percentage (%)

Testosterone Undecanoate 5.0

                                                         

Polyte oxygenyl hydrogenated sesame oil 12.0

                                                 

Preparation: Dissolve testosterone undecanoate in glyceryl caprylate, add polyoxyethylene hydrogenated castor oil and polysorbate-85 to form a uniform solution, mix the solution with 20ml 37℃ 0.1mol/L hydrochloric acid, and use a glass rod Stir gently to obtain a white emulsion with a particle size of about 5 μm.

Example 9: Components % by mass (%)

                                                               

Vegetable oil 38.5

Polyte oxygenyl hydrogenated sesame oil 13.2

                                                                       

Preparation: Dissolve testosterone undecanoate in vegetable oil, add polyoxyethylene hydrogenated castor oil and polysorbate-85 to form a uniform drug solution, mix the drug solution with 20ml of 0.1mol/L hydrochloric acid solution at 37°C, and use a glass rod Stir gently to obtain a transparent emulsion with blue opalescence. The particle size is around 2 μm.

Example 10: Components Mass percentage (%)

                                                               

Vegetable Oil 9.0

Polyoxy ethylene hydrogenated sesame oil 25.0

                                                                 

Preparation: Dissolve testosterone undecanoate in vegetable oil, add polyoxyethylene hydrogenated castor oil and polysorbate-85 to form a uniform drug solution, mix the drug solution with 20ml of 0.1mol/L hydrochloric acid solution at 37°C, and use a glass rod Stir gently to obtain a transparent emulsion with blue opalescence. The particle size is around 2 μm.

Example 11: Components % by mass (%)

                                                                   

Vegetable oil 30.0

Polyoxy ethylene hydrogenated sesame oil 40.0

Polyshan pearl ester-85 20.0

Preparation: Dissolve testosterone undecanoate in vegetable oil, add polyoxyethylene hydrogenated castor oil and polysorbate-85 to form a uniform drug solution, mix the drug solution with 20ml of 0.1mol/L hydrochloric acid solution at 37°C, and use a glass rod Stir gently to obtain a white emulsion with a particle size of about 5 μm.

Claims (7)

1. testosterone undecanoate self-emulsifying soft capsule composition, is made up of testosterone undecanoate, oil phase, emulsifier, is characterized in that: emulsifier is nonionic surfactant, and the mass ratio that each component accounts for is ten The content of testosterone monoacid is 0.1-20%, the content of oil phase is 7-80%, and the content of non-ionic surfactant is 17-90%. 2. testosterone undecanoate self-emulsifying soft capsule composition according to claim 1, is characterized in that: oily phase is selected from vegetable oil, any in the middle and long chain triglyceride fatty acid glyceride containing 8-10 carbon . 3. testosterone undecanoate self-emulsifying soft capsule composition according to claim 1 is characterized in that: nonionic surfactant is selected from polysorbate-80, polysorbate-85, polysorbate-20 , any one of polyoxyethylene hydrogenated castor oil. 4. according to the arbitrary described testosterone undecanoate self-emulsifying soft capsule composition of claim 1-3, it is characterized in that: the nonionic surfactant that composition selects to mix is made emulsifier. 5. according to the arbitrary described testosterone undecanoate self-emulsifying soft capsule composition of claim 1-4, it is characterized in that: the mass ratio of oil phase and emulsifier is 1: 0.25-10. 6. according to the arbitrary described testosterone undecanoate self-emulsifying soft capsule composition of claim 1-4, it is characterized in that: the mass ratio of two kinds of emulsifiers in the mixed emulsifier is 1: 0.3-5. 7. the preparation method of the testosterone undecanoate self-emulsifying soft capsule composition described in claim 1-6: testosterone undecanoate is dissolved in the oil phase, and emulsifier is mixed in proportion to form a uniform solution, namely self-emulsification system, take the solution and mix it with 0.1mol/L hydrochloric acid solution, and form an oil-in-water emulsion by gentle stirring, and the particle size of the emulsion droplet is below 5 μm.