CN1509720A - Progesterone capsules and preparation method - Google Patents

Abstract

The invention discloses a capsule preparation containing progesterone, which contains a transparent liquid made of progesterone, a solubilizer, a surfactant and other auxiliary materials, and is made of gelatin as an outer wrapping material. The progesterone capsule developed by the present invention can be used orally, and its bioavailability in dogs is 2.79 times that of the commercially available progesterone injection, and has the characteristics of small dosage and high bioavailability. The progesterone capsules can be used for various diseases or symptoms caused by lack of progesterone or insufficient corpus luteum function.

Description

Progesterone capsules and preparation method

technical field

The invention relates to a progesterone preparation.

Background technique

Progesterone, the English name is progesterone, and its chemical name is pregnant-4-ene-3,20-dione. It has the general effect of progestin and is used for menstrual disorders, such as amenorrhea and dysfunctional uterine bleeding, luteal insufficiency, threatened abortion and habitual abortion, treatment of premenstrual tension syndrome, and the use of estrogen cycle against the effect of pure estrogen The role of the inner membrane. It is also used to increase the pregnancy rate of animals.

However, progesterone is very poor in water solubility, and the absorption amount after oral administration is small and is quickly metabolized and inactivated by the liver. Therefore, the clinically used dosage form is injection, which is very inconvenient for patients, especially long-term users, and it is easy to cause drug accumulation in local muscle composition Cause lump pain etc.

Generally, when a water-soluble drug is absorbed by the digestive tract in the body, its absorption rate is directly proportional to its dissolution rate. Progesterone is a water-insoluble drug, which is poorly absorbed in the digestive tract, so currently only injections are available for injection in clinical practice in China. In order to improve the dissolution rate, it is necessary to increase its hydrophilicity, so the surfactant with high HLB value and polyalcohol with good solubility are used to make solution-type progesterone capsules.

In view of the above situation, foreign countries have developed and listed oral capsule UTROGESTAN (an Qitan, patent No. US4196188) instead of injections. It improves the oral bioavailability of progesterone to a certain extent, but the price is expensive, and the content is a suspension, so the dosage is large, 200 mg per day.

Contents of the invention

The technical problem to be solved by the present invention is to disclose a new progesterone preparation, i.e. progesterone solution-type capsules. The capsules are high bioavailability capsules made of progesterone as the main drug, combined with non-ionic surfactants and other solubilizers to improve drug dissolution.

The progesterone capsule preparation developed by the present invention is a capsule containing a liquid solution of pharmacologically active components. The capsule is made from the contained pharmacologically active component solution and the outer wrapping material according to the common capsule preparation process.

The contained pharmacologically active component solution includes the pharmacologically active component progesterone and auxiliary materials. The auxiliary materials used include solvents for dissolving progesterone such as polyethylene glycol 400 and polyethylene glycol 600, which increase the hydrophilicity of the drug Solubilizers such as polysorbate-20, polysorbate-80 and other surfactants.

The progesterone capsules developed by the present invention, based on 1000 capsules, contain 2-15g of progesterone, 5-200g of polysorbate-20 and polysorbate-80, and the rest are polyethylene glycol-400 Or polyethylene glycol-600 or a mixture of both, for example, on the basis of every 1000 capsules, it contains 5g of progesterone, 10g of polysorbate-20, and the rest is polyethylene glycol-400.

The preparation of the present invention is prepared as follows: mix the components according to the above ratio, heat at 20-80°C and stir constantly, after the progesterone is dissolved, take an appropriate amount and fill it into the capsules with a rotary mode capsule manufacturing machine.

Investigate the stability of the progesterone capsules prepared by the present invention:

Remove the outer packaging of this product and place it directly under the conditions of light 3500LX, room temperature and air, 40°C, 25°C RH92.5% and RH75% for 10 days each, and compare with the original sample for traits, content color, fragmentation, collapse Solution time limit, content determination, chromatographic examination of degradation products, etc., were basically stable. Under the packaging conditions of the market, accelerated three months at 40°C RH75% and stored at room temperature for 24 months, and regularly observed and measured according to the established quality and temperature standards, the product is basically stable.

Progesterone is made into solution A, B, C, D, E of polyethylene glycol 400 of polysorbate 20 of 2% different ratios and is made need testing solution, presses the 2000 version Chinese Pharmacopoeia appendix XC dissolution method second Dissolution test by method: Measure 300ml of degassed distilled water, inject it into each operation container, heat to keep the water at 37±0-5℃, accurately weigh 2g of the test solution, and inject it into 6 operation containers respectively Immediately start the rotation (50 rev/min) and start timing. When 30 minutes, draw an appropriate amount of solution at the prescribed sampling point, and immediately filter through a 0.45um microporous membrane, and get the continued filtrate to measure by spectrophotometry. Calculate the dissolution percentage each time, and the results are shown in the following table:

The dissolution percentage (%, 30 minutes) of Anqitan capsules and each prescription in water Anchitan Contents A B C D. E. 1 0.75 13.84 9.72 25.21 29.89 58.41 2 0.33 15.23 8.64 24.30 32.42 58.19 3 0.25 14.21 17.47 24.48 27.07 55.09 4 0.47 4.90 17.48 24.83 27.33 53.06 5 0.38 13.89 4.89 25.52 29.53 61.42 6 0.45 13.14 15.48 24.99 24.40 60.08 average 0.44 14.20 17.36 24.89 28.44 57.83 SD 0.17 0.76 1.86 0.45 2.78 3.24

It can be seen from the table that the dissolution rates of Anqitan micropowder capsules (contents) and prescriptions A, B, C, D, and E were 0.44±0.17%, 14.20±0.76%, 17.36±1.86%, and 24.89±0.17% respectively in 30 minutes. 0.45%, 28.44±2.78%, 57.83±3.24%. Explain that prescription D is the best.

Progesterone capsules of the present invention and Anqitan capsules are according to Chinese Pharmacopoeia 2000 edition two appendix X dissolution method third method, with 0.1mol/L hydrochloric acid 250ml as solvent, rotating speed is 150 revolutions per minute, operate according to law, After 45 minutes, take the continued filtrate and measure it according to high performance liquid chromatography (Appendix VD). Calculation of the dissolution of the two see the table below.

See the table below for the results of the comparative determination of the dissolution rate of progesterone capsules and "Anqitan" capsules in 0.1mol/L HCl. preparation Dissolution (%) Mean(%)～SD Angelina 0.63 0.48 1.42 0.30 0.65 0.70±0.43 This product 88.56 73.26 90.44 75.41 71.18 75.56 79.07±8.26

Comparative determination results of the absolute dissolution rate of progesterone capsules and "Anqitan" capsules in 0.1mol/L preparation Dissolution (%) Mean(%)～SD Angelina 0.63 0.48 1.42 0.30 0.65 0.70 This product 4.43 3.66 4.53 3.77 3.56 3.78 3.96

It can be seen from the table that in 0.1mol/L HCl, the absolute dissolution rate of the progesterone capsules of the present invention is 5.66 times that of the imported "Anqitan" capsules, which is actually a high-efficiency preparation.

Progesterone capsule animal relative bioavailability experimental research of the present invention:

Taking 6 domestic dogs as test objects, adopting the same body crossover test method, respectively single-cross fasting gavage administration of progesterone capsules of the present invention, containing 100 mg of progesterone, or intramuscular injection of 100 mg of progesterone as a control preparation, radioimmunoassay The drug concentration in plasma was determined at different times by the method, and the main pharmacokinetic parameters were obtained according to the plasma concentration-time data.

Calculation results show: the _Cmax of progesterone in the progesterone capsules of the present invention is 247.31±39.73 (ng/ml), _Tmax is 0.88±0.56(h), t1 _/2 is 2.98±0.45(h), _{AUC0 ～10} is 901.74±162.29 (ng/ml.h), AUC _0～∞ is 351.18±30, 74 (ng/ml, h). The C _max of progesterone in progesterone injection is 119.06±20.22(ng/ml), T _max is 0.29±0.10(h), t _1/2 is 2.04±0.59(h), AUC _0～10 is 335.69±77.31 (ng/ml.h), AUC _0～∞ was 373.18±87.82 (ng/ml.h).

Statistical _analysis and bioequivalence evaluation were carried out on the above-mentioned main pharmacokinetic parameters, _and the results showed that there were significant statistical differences (P( _0.05 ) The average relative bioavailability of progesterone in the progesterone capsules of the present invention is 279.60 ± 58.62%, and the 90% credible limit of its bioavailability parameter value is 223.35～523.01%.It can be seen that the corpus luteum of the present invention Ketone capsules have the characteristics of low dosage, fast absorption, high blood concentration and bioavailability.

Detailed ways

Example 1

A progesterone-containing capsule is made of a progesterone transparent solution made of progesterone and auxiliary materials, and gelatin as outer wrapping materials.

Example 2

The auxiliary materials described in Example 1 include solvents for dissolving progesterone such as polyethylene glycol 400 or polyethylene glycol 600 or a mixture of the two; solubilizers such as polysorbate 20 or polysorbate 80 and other surfactants.

Example 3

The capsules described in Example 2 contain 5 g of progesterone per 1000 capsules, 10 g of polysorbate-20 or polysorbate 80, and the rest are polyethylene glycol-400 or polyethylene glycol 600 or two a mixture of.

Claims (4)

1. A capsule containing progesterone is composed of a liquid solubilizer with a pharmacologically active component and an outer wrapping material, and is characterized in that the liquid solution with a pharmacologically active component contained in it is made of progesterone and the progesterone solution made of auxiliary materials; the outer wrapping material is gelatin, or gelatin, propylene glycol, or other clinically acceptable capsule outer wrapping materials. 2. The capsule containing progesterone according to claim 1 is characterized in that said adjuvant comprises a solvent for dissolving progesterone, such as Polyethylene Glycol 400, Polyethylene Glycol 600, solubilizer such as polysorbate Ester-20, polysorbate-80 surfactants. 3. The progesterone-containing capsules according to claim 2, characterized in that every 1000 capsules contain progesterone 2～15g, polysorbate-20 or polysorbate-80 is 5～200g, and the rest It is polyethylene glycol-400 or polyethylene glycol-600 or a mixture of both. 4. The capsule containing progesterone according to claim 2, characterized in that every 1000 capsules contain progesterone 5g, polysorbate-20 or polysorbate-80 is 10g, and all the other are polyethylene glycol Alcohol-400 or polyethylene glycol 600 or a mixture of both.