CN108186553B

CN108186553B - Long-acting progesterone suppository and preparation method thereof

Info

Publication number: CN108186553B
Application number: CN201810148692.2A
Authority: CN
Inventors: 张蜀; 邓红; 朱秀城
Original assignee: Guangdong Pharmaceutical University
Current assignee: Guangdong Pharmaceutical University
Priority date: 2018-02-13
Filing date: 2018-02-13
Publication date: 2020-10-02
Anticipated expiration: 2038-02-13
Also published as: CN108186553A

Abstract

The invention discloses a long-acting progesterone suppository which is mainly prepared from the following components in percentage by weight: 1-6% of progesterone, 2-5% of an adhesive and 89-97% of a suppository matrix. The invention also provides a preparation method of the long-acting progesterone suppository. The long-acting suppository has the advantages of small irritation, strong adhesiveness, long retention time, small leakage amount, and slow drug release.

Description

Long-acting progesterone suppository and preparation method thereof

Technical Field

The invention relates to a progesterone suppository, in particular to a long-acting progesterone suppository. The invention also relates to a preparation method of the long-acting progesterone suppository.

Background

Progesterone (P), also known as Progesterone, gestagen, pregnenedione, is secreted primarily by the ovarian corpus luteum and can also be produced by the placenta and glial cells of the adrenal gland, testis, and central nervous system. Progesterone is a natural progestogen secreted by the ovarian corpus luteum and placenta, has a significant morphological effect on estrogen-stimulated endometrium in vivo, is essential for maintaining pregnancy, and is the most important sex hormone drug for the corpus luteum to support. Studies have shown that a certain level of progestogen is critical to the maintenance of pregnancy, with abortion resulting from removal of the corpus luteum 7 weeks before pregnancy, and pregnancy maintained by exogenous progestogen supplementation. Progesterone is clinically used for the treatment of various diseases caused by luteal insufficiency, such as menstrual disorder, amenorrhea and dysfunctional uterine bleeding, luteal insufficiency, threatened abortion and habitual abortion (caused by luteal insufficiency), premenstrual tension syndrome, postpartum depression, etc., and luteal support for Assisted Reproductive Therapy (ART).

Currently, progesterone preparations are marketed as injections, capsules, soft capsules, suppositories, vaginal sustained-release gels, vaginal tablets, intrauterine contraceptive systems, and the like. A large number of clinical studies show that the oral administration of the progesterone has liver first-pass effect, low bioavailability and easy toxic and side effects when the dosage is large; the progesterone injection has definite curative effect, but has large irritation during injection, causes pain and discomfort of patients, and has low medication compliance of patients after long-term use; the curative effect of vaginal administration is equivalent to that of injection administration, the administration compliance is high, and in ART corpus luteum support, the vaginal local administration is the only administration route which can replace intramuscular injection at present. Most of common vaginal preparations adopt a single water-soluble matrix or a single fatty matrix, and the medicaments are released quickly, have no adhesion, are easy to be cleared by the vagina and are discharged out of the body quickly, so that the residence time of the medicaments in the vagina is short, the leakage amount is large, the effective dose is reduced, the effective time is short, and the effect of medicament treatment is influenced.

Therefore, the research and development of the long-acting progesterone dosage form which is long-lasting, slow-releasing, economical and effective for vagina has good clinical application prospect.

Disclosure of Invention

The invention aims to provide a progesterone long-acting suppository for vagina, which has low irritation, strong adhesiveness, long retention time, small leakage and slow drug release.

The second purpose of the invention is to provide a preparation method of the long-acting progesterone suppository.

In order to achieve the first object, the present invention provides the following technical solutions: a long-acting progesterone suppository comprises the following components in percentage by weight:

1-6% of progesterone;

2-5% of an adhesive;

89-97% of suppository matrix.

Wherein, the progesterone adopts progesterone micro powder with the particle size less than or equal to 75 mu m.

Wherein the adhesive is one or more of polycarbophil, carbomer, hydroxypropyl methylcellulose, chitosan, sodium carboxymethylcellulose, polyvinylpyrrolidone, sodium hyaluronate, sodium alginate, guar gum, xanthan gum and pectin.

Preferably, the adhesive is a combination of a strong-adhesion adhesive and a skeleton adhesive, the strong-adhesion adhesive is one or two of polycarbophil and carbomer, and the skeleton adhesive is one or more of hydroxypropyl methylcellulose, chitosan, sodium carboxymethylcellulose, polyvinylpyrrolidone, sodium hyaluronate, sodium alginate, guar gum, xanthan gum and pectin.

The mass fractions of the strong-adhesion adhesive and the skeleton-type adhesive are respectively as follows:

10 to 40% of a strongly adhesive binder

60-90% of framework type adhesive.

Wherein the suppository matrix is an emulsion matrix.

Wherein the emulsion matrix can be selected from matrix with hydrophilicity and emulsification performance, such as polyoxyl (40) stearate. In order to further improve the sustained-release long-acting effect of the suppository, the emulsion-type base is composed of a water-soluble base, a fatty base and a surfactant. Wherein the mass fractions of the water-soluble matrix, the fatty matrix and the surfactant are as follows:

67-89.5% of water-soluble matrix

10-30% of fatty matrix

0.5-3% of a surfactant.

The water-soluble matrix is one or more of polyethylene glycol, poloxamer, polyoxyl stearate and glycerogelatin. The polyethylene glycol matrix (PEG) comprises one or more of PEG200, PEG400, PEG1500, PEG4000 and PEG 6000. The poloxamer matrix is composed of poloxamer and propylene glycol at any ratio, and contains poloxamer 108/124/127/188/237/338/407.

Wherein the fatty matrix is one or more of semisynthetic fatty acid glycerides, natural fatty acid esters and hydrogenated oil. The semisynthetic fatty acid glycerides include glycerol fatty acid esters such as glycerol monostearate, glycerol monolaurate, glycerol behenate, coconut oil ester, palmitate, and the like; and sucrose fatty acid esters such as sucrose monostearate, sucrose monopalmitate, etc. The natural fatty acid ester comprises cacao butter, fructus Citri Tangerinae, Chinese tallow, fructus Foeniculi, Arecae semen lipid, etc.

The surfactant is preferably a nonionic surfactant with the HLB value within the range of 8-40, and the nonionic surfactant is one or more of polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty alcohol esters and polyoxyethylene polypropylene copolymers. The polyoxyethylene sorbitan fatty acid esters (tweens) comprise tween 80, tween 60, tween 65 and the like; the polyoxyethylene fatty alcohol ether comprises Bigze 35, peregal O, an emulsifier OP and the like; the polyoxyethylene fatty acid esters comprise maize 52, maize 53, maize 45 and the like; polyoxyethylene polypropylene copolymers including poloxamer 188, poloxamer 237, poloxamer 407, etc.

In order to achieve the second object, the present invention provides the following technical solutions: the preparation method of the progesterone long-acting suppository comprises the following steps:

step 1: heating suppository matrix in water bath, and stirring to melt;

step 2: adding progesterone and an adhesive into the fused suppository matrix obtained in the step (1) in a water bath, and uniformly mixing at the rotating speed of 700-5000 r/min to obtain a mixed solution;

and step 3: and (3) cooling the mixed solution obtained in the step (2) to be viscous, injecting the mixed solution into a suppository mold at one time, cooling to 20-25 ℃, and demolding to obtain the long-acting progesterone suppository.

Compared with the traditional method, the method has the following advantages:

1. the progesterone long-acting suppository provided by the invention can slowly and permanently release progesterone, reduce toxic and side effects, reduce administration times and increase the medication compliance of patients.

2. The adhesive is added into the long-acting progesterone suppository provided by the invention, so that the suppository can absorb water and swell in a high-water-content vaginal environment, and is adhered to vaginal mucosa, thereby achieving the effects of increasing retention time and retention amount and increasing the action amount and curative effect of the medicament. Furthermore, the invention preferably uses the combination of the adhesive with strong adhesiveness and the skeleton type adhesive as the adhesive of the suppository, so that when the suppository is applied, the adhesive can rapidly absorb water and swell in a high-water-content vaginal environment and adhere to the vaginal mucosa, and the effect of further increasing the retention time and the retention amount is further improved. Therefore, compared with the common suppository, the long-acting progesterone suppository provided by the invention has higher adhesiveness, so that the suppository can be retained at the administration part for a long time, the leakage of the medicament is reduced, and the curative effect of the medicament is improved.

3. Progesterone is a fat-soluble drug, and if a water-soluble matrix is singly used, the matrix is quickly dissolved in body fluid, so that the drug is quickly released, and the purpose of long-time slow release cannot be met; the use of a fatty matrix alone results in a slow and incomplete release of the drug due to the slow melting of the matrix. The present invention therefore employs an emulsion-type base as a suppository base. The emulsion base contains a large proportion of water-soluble matrix and a small proportion of fatty matrix, has high hydrophilicity and low lipophilicity, so that part of the progesterone is dissolved in the fatty matrix, and the other part of the progesterone is dispersed in the water-soluble matrix, therefore, in the application of the suppository, the progesterone dispersed in the water-soluble matrix is firstly released, and the progesterone with a small proportion of the progesterone dissolved in the fatty matrix is slowly released along with the melting of the suppository, so that the medicament achieves a certain slow release effect.

4. The surface active agent is added into the suppository matrix, so that the surface tension between the water-soluble matrix and the fatty matrix can be reduced, and the water-soluble matrix and the fatty matrix are uniformly mixed; on the other hand, fat-soluble progesterone can be more uniformly dispersed in the suppository matrix, so that the drug loading is larger than that of the common suppository.

5. The prescription process of the long-acting progesterone suppository is simple, and industrial mass production can be realized.

Drawings

Fig. 1 is a graph of the cumulative release of the long acting and ordinary progesterone suppositories of example 1.

Detailed Description

The technical solution of the present invention will be described in further detail with reference to the following embodiments.

In the following examples, the in vitro adhesion time detection method: zhuxiucheng research on in vitro evaluation method of progesterone bioadhesive sustained-release suppository, university of Guangdong pharmacy, 2017,33(2), 148-.

The drug release rate is measured by a blue-transfer method after 24h, 500mL of freshly degassed 0.5% SDS-4 buffer is used as a release medium, the temperature is 37.0 +/-0.5 ℃, and the rotating speed is 30 r/min. Precisely weighing the long-acting suppository, placing the long-acting suppository in a basket, sampling 5mL in 1 st, 2 nd, 4 th, 6 th, 8 th, 12 th and 24 th hours respectively, immediately filtering by using a 0.22 mu m filter membrane, timely supplementing an equivalent isothermal medium, and determining according to the following chromatographic conditions: a chromatographic column: dimonosil C18 column (4.6 mm. times.250 mm, 5 μm); mobile phase: methanol-water (80: 20); flow rate: 1 mL/min; detection wavelength: 245 nm; sample introduction amount: 10 mu L of the solution; column temperature: at 30 ℃.

Example 1

1.5% of progesterone; 5% of adhesive; and 93.5 percent of suppository matrix.

The adhesive consists of 10% polycarbophil and 90% hydroxypropyl methylcellulose. The suppository matrix is polyoxyl (40) stearate.

Step 1: the suppository base is melted by heating in a water bath and stirring.

Step 2: and (3) under a water bath, adding the progesterone and the adhesive into the molten suppository matrix obtained in the step (1), and uniformly mixing at the rotating speed of 700r/min to obtain a mixed solution.

And step 3: and (3) cooling the mixed solution obtained in the step (2) to be sticky, injecting the mixture into a suppository mold at one time, cooling to 25 ℃, and demolding to obtain the long-acting progesterone suppository.

As a result: the obtained long-acting suppository is smooth and complete milky white suppository, and the in vitro adhesion time is 82.54 s.

The cumulative release percentage of the prepared long-acting and common progesterone suppository is shown in figure 1. The result shows that the long-acting progesterone suppository has no burst release within 2 hours, and the drug release rate within 24 hours is 90.7%.

Example 2

4% of progesterone; 3% of adhesive and 93% of suppository matrix.

The adhesive is polycarbophil. The suppository base consists of 84.5% poloxamer 407, 0.5

% polysorbate

60 and 15% mixed fatty acid glyceride type 38.

Step 1: the suppository base is melted by heating in a water bath and stirring.

Step 2: and (3) adding the progesterone and the adhesive into the molten suppository matrix obtained in the step (1) in a water bath, and uniformly mixing at the rotating speed of 5000r/min to obtain a mixed solution.

And step 3: and (3) cooling the mixed solution obtained in the step (2) to be sticky, injecting the sticky mixed solution into a suppository mold at one time, cooling to 20 ℃, and demolding to obtain the long-acting progesterone suppository.

The result shows that the long-acting suppository of the progesterone is smooth and complete milky white suppository, the in vitro adhesion time is 83.33s, and the drug release rate is 91.1% after 24 h.

Example 3

6% of progesterone; 2% of adhesive; 92% of suppository matrix.

The adhesive is composed of 20% carbomer 934 and 80% chitosan. The suppository matrix is composed of 79% polyethylene glycol 4000, 1

% polysorbate

80 and 20% mixed fatty glyceride 40.

Step 1: the suppository base is melted by heating in a water bath and stirring.

Step 2: and (3) adding the progesterone and the adhesive into the molten suppository matrix obtained in the step (1) in a water bath, and uniformly mixing at the rotating speed of 800r/min to obtain a mixed solution.

And step 3: and (3) cooling the mixed solution obtained in the step (2) to be sticky, injecting the sticky mixed solution into a suppository mold at one time, cooling to 22 ℃, and demolding to obtain the long-acting progesterone suppository.

The result shows that the long-acting suppository of the progesterone is smooth and complete milky white suppository, the in vitro adhesion time is 110.62s, and the cumulative release rate of the medicine is about 90.4 percent after 24 hours.

Example 4

1% of progesterone; 5% of adhesive; 94% of suppository matrix.

The adhesive is carbomer 974P. The suppository matrix is composed of 89% of glycerogelatin, 1% of peregal O-25 and 10% of glyceryl behenate.

Step 1: the suppository base is melted by heating in a water bath and stirring.

Step 2: and (3) adding the progesterone and the adhesive into the molten suppository matrix obtained in the step (1) in a water bath, and uniformly mixing at the rotating speed of 2500r/min to obtain a mixed solution.

And step 3: and (3) cooling the mixed solution obtained in the step (2) to be sticky, injecting the mixture into a suppository mold at one time, cooling to 24 ℃, and demolding to obtain the long-acting progesterone suppository.

As a result: the long-acting progesterone suppository is a smooth and complete white suppository, the in vitro adhesion time is 103.30s, and the cumulative release rate of the 24h medicament is 90.8%.

Example 5

6% of progesterone; 5% of adhesive; 89% of suppository matrix.

The adhesive consists of 10% polycarbophil and 90% guar gum. The suppository base is composed of 74.5% polyoxyl (40) stearate, 0.5% poloxamer 188 and 25% cocoa butter.

Step 1: the suppository base is melted by heating in a water bath and stirring.

Step 2: and (3) adding the progesterone and the adhesive into the molten suppository matrix obtained in the step (1) in a water bath, and uniformly mixing at the rotating speed of 3600r/min to obtain a mixed solution.

And step 3: and (3) cooling the mixed solution obtained in the step (2) to be sticky, injecting the sticky mixed solution into a suppository mold at one time, cooling to 23 ℃, and demolding to obtain the long-acting progesterone suppository.

As a result: the long-acting progesterone suppository is a smooth and complete white suppository, the in vitro adhesion time is 78.36s, and the cumulative release rate of the 24h medicament is 91.5%.

The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The above-described embodiments of the present invention are to be considered as illustrative and not restrictive, and therefore all slight modifications, equivalent changes and modifications made to the above examples in accordance with the spirit of the present invention are within the scope of the present invention.

Claims

1. A long-acting progesterone suppository is characterized by being mainly prepared from the following components in percentage by weight:

1-6% of progesterone;

2-5% of an adhesive;

89-97% of suppository matrix;

the suppository matrix is an emulsion matrix which comprises polyoxyl (40) stearate, or the emulsion matrix consists of a water-soluble matrix, a fatty matrix and a surfactant; wherein the mass fractions of the water-soluble matrix, the fatty matrix and the surfactant are as follows:

67-89.5% of water-soluble matrix

10-30% of fatty matrix

0.5-3% of a surfactant;

the adhesive is a combination of a strong-adhesion adhesive and a skeleton-type adhesive, and the mass fractions of the strong-adhesion adhesive and the skeleton-type adhesive are respectively as follows:

10 to 40% of a strongly adhesive binder

60-90% of a framework type adhesive;

the adhesive with strong adhesiveness is one or two of polycarbophil and carbomer, and the skeleton type adhesive is one or more of hydroxypropyl methylcellulose, chitosan, sodium carboxymethylcellulose, polyvinylpyrrolidone, sodium hyaluronate, sodium alginate, guar gum, xanthan gum and pectin; the water-soluble matrix is one or more than two of polyethylene glycol, poloxamer, polyoxyl stearate and glycerogelatin; the fatty matrix is one or more of semisynthetic fatty acid glycerolipid, natural fatty acid ester and hydrogenated oil; the surfactant is a nonionic surfactant with the HLB value within the range of 8-40, and comprises one or more of polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid esters and polyoxyethylene polypropylene copolymers.

2. The long-acting progesterone suppository according to claim 1, wherein the progesterone is micropowder with a particle size less than or equal to 75 μm.

3. A method of preparing a long acting suppository of progesterone according to claim 1 or 2 comprising the steps of:

step 1: heating suppository matrix in water bath, and stirring to melt;

step 2: adding progesterone and an adhesive into the molten suppository matrix obtained in the step 1 in a water bath, and uniformly mixing at the rotating speed of 700-5000 r/min to obtain a mixed solution;