WO2011072509A1

WO2011072509A1 - Progesterone formulation composition and preparation method thereof

Info

Publication number: WO2011072509A1
Application number: PCT/CN2010/072728
Authority: WO
Inventors: 邓金明; 吴海英
Original assignee: 浙江爱生药业有限公司
Priority date: 2009-12-14
Filing date: 2010-05-13
Publication date: 2011-06-23
Also published as: CN102091054A; CN102091054B

Abstract

A progesterone formulation composition and the preparation method thereof are disclosed. The composition is composed of progesterone oil content prepared from progesterone, non-polar solvents and solubilizers and encapsulating materials. The non-polar solvents are vegetable oils or/and animal oils. The solubilizer is lecithin or/and beeswax. Said composition can be administered orally for the treatment of diseases or disorders induced by progestogen insufficiency or inadequate luteal function.

Description

Progesterone preparation composition and preparation method thereof

The present invention relates to the field of medicine, and in particular to a progestin preparation composition having high dissolution and a preparation method thereof. Background technique

Progesterone (English name progesterone, chemical name is pregnant _4_ene_3, 20-dione) is a natural progesterone with a general role of progesterone, widely used in the treatment of threatened abortion, habitual abortion, artificial insemination Progesterone or luteal function, infertility, premenstrual tension syndrome, anovulatory dysfunctional uterine bleeding, anovulatory amenorrhea, endometrial hyperplasia, endometrial adenocarcinoma, endometriosis and menopausal syndrome The disease or symptom caused.

Progesterone is readily soluble in non-polar solvents and is almost insoluble in water. The existing progesterone preparations include tablets and capsules, but they are extremely poorly absorbed in the stomach after oral administration, and are easily metabolized by the liver to be inactivated, and are basically unusable in clinical use. Therefore, clinical use of oily injections is mainly used. . However, because the oily injection is not easily absorbed, it may cause the injection to accumulate in the local muscles after injection, forming a mass, which inevitably aggravates the patient's pain.

U.S. Patent No. 4,196,188 discloses a progesterone oral capsule (referred to as UTR0GESTAN), which can replace the above injection, and has higher bioavailability than the above progesterone preparation, and there are similar dosage forms of progesterone oral capsules on the market in China. The progesterone micropowder in the above capsule is suspended in an oil solution, and the patient needs to take 200 mg of progesterone oral capsule every day to have an effective therapeutic effect, and the excess progesterone which cannot be absorbed by the patient is mainly metabolized by the liver. The damage to the liver is large; at the same time, metabolites are prone to many adverse reactions in patients, so this oral capsule is still limited in clinical application.

In carrying out the present invention, the inventors have found that the above-mentioned progesterone-containing drug has at least the following problems:

(1) Large dosage: For the progesterone oral capsule with the patent number US4196188, the patient needs to take 200mg of progesterone oral capsule every day to have an effective therapeutic effect, and the dosage is larger; the corpus luteum that cannot be absorbed by the patient Ketones are inactivated by rapid metabolism of the liver;

(2) Low dissolution: The existing tablets and capsule type progesterone preparations have poor absorption in the stomach of the patient after oral administration;

(3) Low bioavailability: The existing progesterone preparation has low dissolution in the patient, affecting absorption. The 200 mg progesterone oral capsule that the patient needs to take every day is only 20 mg of the injection, and the rest cannot be absorbed by the patient. The progesterone is inactivated by rapid metabolism of the liver, and it can be seen that the utilization rate of progesterone in the above progesterone preparation or progesterone oral capsule is low;

(4) Many adverse reactions: The excess progesterone which cannot be absorbed by the patient in the above progesterone preparation or progesterone oral capsule is rapidly metabolized by the liver, and the damage to the liver is large. The adverse drug reactions were mainly dizziness and bloating, the incidence of dizziness was 10.3%, and the incidence of bloating was 17.2%.

Summary of the invention The object of the present invention is to solve the defects in the prior art that the dosage is large, the dissolution rate is low, the bioavailability is low, and the adverse reactions are many. The progesterone preparation composition with high dissolution rate and the preparation method thereof are proposed to realize the dosage. Small, high dissolution, high bioavailability and low adverse reactions.

In order to achieve the above object, the present invention provides a progesterone preparation composition comprising a liquid solubilizing agent content having a pharmacologically active component and an outer wrapping material, characterized in that: the liquid containing the pharmacologically active component is increased The solvent content is a progesterone oil solution prepared from progesterone and an auxiliary material; the auxiliary material is a non-polar solvent and a solubilizing agent, the non-polar solvent is vegetable oil or/and animal oil, and the solubilizing agent is lecithin or / and beeswax;

The progesterone is contained in an amount of 2 to 30 g, the solubilizing agent is 0 to 180 g, and the nonpolar solvent is 75 to 1000 g per 1000 parts of the composition. Preferably, the progesterone contains 5-20 g, the solubilizer is 0-100 g, and the non-polar solvent is 80-800 g per 1000 formulation compositions.

Preferably, 5 g of progesterone is contained per 1000 parts of the formulation composition, the solubilizing agent is 0-50 g, and the nonpolar solvent is 80-200 g. Preferably, 10 g of progesterone is contained per 1000 parts of the preparation composition, the solubilizing agent is 0-80 g, and the non-polar solvent is 100-500 g.

Preferably, it contains 20 g of progesterone, a solubilizing agent of 0-100 g, and a non-polar solvent of 400-800 g per 1000 parts of the formulation composition.

The vegetable oil is vegetable oil for peanut oil, soybean oil, rapeseed oil, corn oil, olive oil, sunflower oil, sesame oil, linseed oil, cottonseed oil, rice bran oil, coconut oil, camellia seed oil, canola oil One or more of pepper oil, chili oil, and the like.

The animal oil is one or more of animal fat oils such as lard, butter, sheep oil, chicken oil, and duck oil.

The lecithin is soy lecithin or egg yolk lecithin.

The particle size of 90% of the progesterone micropowder in the progesterone micropowder is less than 10 μm.

The preparation form is a soft capsule, a liquid capsule or a dropping pellet, and the outer coating is gelatin, or gelatin and glycerin, or other clinically acceptable capsule outer wrapping material.

The preparation method of the above progesterone preparation composition comprises: weighing the components of the content in proportion, mixing and stirring to obtain a progesterone oil solution, and filling the progesterone oil solution on the soft capsule or the hard capsule or the dropping pills on average. in.

The mixture was homogenized by ultrasonic assisted dissolution.

In general, increasing the water solubility of a drug increases its absorbance, but for a fat-soluble drug, lipolysis is the most important way of drug transport. A liposoluble drug can be directly dissolved into a lipid and passed through the cell membrane. The transport speed is mainly related to the fat solubility of the drug. The greater the fat solubility, the easier it is to spread, and the more easily it is absorbed by the lipid membrane of the capillaries; the fat content of the fat-soluble drug preparation affects the degree of absorption, and the progesterone is a fat-soluble drug. , high solubility in non-polar solvents. The progesterone composition of the present invention uses lecithin or beeswax and vegetable oil or animal oil as a non-polar solution of progesterone The agent, through a large number of experiments, proves that by adjusting the ratio of the three, when the progesterone composition exhibits an oil solution state, its bioavailability is higher. The progesterone in the progesterone composition of the present invention can be improved in the patient by containing a non-polar solvent for dissolving the progesterone fine powder, that is, vegetable oil or animal oil, and a solubilizing agent for increasing the solubility of the progesterone fine powder, that is, lecithin or beeswax. The dissolution and bioavailability in the body can improve the dissolution of progesterone in the gastrointestinal tract and the absorption in the patient, thereby improving the bioavailability of the preparation, increasing the absorption of progesterone and reducing liver metabolism. The burden of excess progesterone makes it possible to achieve a small dosage, high dissolution, high bioavailability and low adverse reactions.

It has been proved by experiments that the dissolution rate of the capsule of the present invention is more than 10 times higher than that of the commercially available product, and human experiments show that the 10 mg/granule of the present invention is bioequivalent to the commercially available 100 mg/granule capsule, which greatly reduces the dosage. At the same time, it reduces the metabolic burden of the liver and reduces the harmful effects of liver metabolites on patients.

detailed description

The preferred embodiments of the present invention are described below, and the preferred embodiments described herein are intended to illustrate and explain the invention.

Progesterone micropowder (commercially available, particle size less than 10 μ πι micropowder accounted for more than 90%)

Soy lecithin, egg yolk lecithin, beeswax

Vegetable oil (peanut oil, soybean oil, rapeseed oil, corn oil, olive oil, sunflower oil, sesame oil, linseed oil, cottonseed oil, rice bran oil, coconut oil, camellia seed oil, canola oil, pepper oil, Chili oil)

Animal oil (lard, butter, sheep oil, chicken oil, duck oil)

The basic idea of the invention: 2-30 g of pharmacologically active progesterone is weighed, and 0-180 g of medicinal excipient lecithin or beeswax is added per 1000 composition, and the rest is non-polar of vegetable oil or animal oil or more. The solvent mixture is 75-1000 g, and ultrasonically dissolved to obtain a progesterone oil solution, and the progesterone oil solution is uniformly filled in a soft capsule to prepare a progesterone capsule of the present invention. In the embodiment, the progesterone micropowder has pharmacological activity, is easily soluble in a non-polar solvent, and is insoluble in water; the vegetable oil is a non-polar solvent for dissolving progesterone micropowder; lecithin or beeswax can be used as a solubilizing agent or surface active a agent for increasing the solubility of progesterone particles in vegetable oils. Example 1

Weigh 2g of progesterone micropowder, 8g of soybean lecithin and 92g of soybean oil, mix the weighed progesterone micropowder, soy lecithin and soybean oil, and dissolve it ultrasonically to obtain progesterone oil solution. Soft mode capsule making machine is used. The obtained progesterone oil solution was uniformly filled in 1000 soft capsules to prepare a progesterone capsule.

Example 2

Weighing 5 g of progesterone microparticles, 30 g of beeswax and 110 g of rapeseed oil and 60 g of pepper oil, mixing the weighed progesterone microparticles, soybean lecithin and rapeseed oil, and ultrasonically dissolving to obtain a progesterone oil solution; Mode capsule making machine, The obtained progesterone oil solution was filled in an average of 1000 soft capsules to prepare a progesterone capsule.

Example 3

Weigh 10g of progesterone micropowder, 100g of egg yolk lecithin and 400g of corn oil, mix the weighed progesterone micropowder, egg yolk lecithin and corn oil, and dissolve it ultrasonically to obtain progesterone oil solution; use soft mode capsule making machine The obtained progesterone oil solution was uniformly filled in 1000 soft capsules to prepare a progesterone capsule.

Example 4

Weighing 20 g of progesterone micropowder and 700 g of lard, mixing the weighed progesterone micropowder and lard, and ultrasonically dissolving to obtain a progesterone oil solution; using a soft mode capsule making machine, the obtained progesterone oil solution The average is filled in 1000 soft capsules to prepare a progesterone capsule.

Example 5

Weighing 5 g of progesterone micropowder, 5 g of egg yolk lecithin, 30 g of peanut oil and 65 g of sunflower oil, and mixing the weighed progesterone micropowder, egg yolk lecithin, peanut oil and soybean oil, and ultrasonically dissolving to obtain a progesterone oil solution; Using the soft mode capsule making machine, the obtained progesterone oil solution was uniformly filled in 1000 soft capsules to prepare the progesterone capsule.

Example 6

Weigh 2g of progesterone micropowder, 10g of beeswax and 90g of chicken oil, mix the weighed progesterone micropowder, beeswax and sunflower oil, and dissolve it ultrasonically to obtain progesterone oil solution. Using soft mode capsule manufacturing machine, we will get The progesterone oil solution was filled in an average of 1000 soft capsules to prepare a progesterone capsule.

Example 7

Weighing 30 g of progesterone micropowder, 150 g of beeswax and 850 g of sesame oil, mixing the weighed progesterone micropowder, beeswax and sesame oil, and ultrasonically dissolving to obtain a progesterone oil solution; using the soft mode capsule making machine, the obtained progesterone The oil solution was filled in an average of 1000 soft capsules to prepare a progesterone capsule.

Example 8

Weighing 4 g of progesterone micropowder, 40 g of beeswax and 80 g of butter and 80 g of sheep oil, mixing the weighed progesterone micropowder, beeswax and corn oil, and ultrasonically dissolving to obtain a progesterone oil solution; using a soft mode capsule making machine, The obtained progesterone oil solution was filled in an average of 1000 soft capsules to prepare a progesterone capsule.

In each of the above embodiments, at least one of vegetable oils such as peanut oil, soybean oil, rapeseed oil, and corn oil, or at least one of lard, butter, sheep oil, and the like, may be used to dissolve the progesterone powder. Soy lecithin, egg yolk lecithin or beeswax can be used as a solubilizing agent for the progesterone fine powder to be dissolved in the above vegetable oil, and can also be used as a surfactant for the progesterone composition of the present invention.

In summary, in the embodiments of the present invention, progesterone micropowder, lecithin or beeswax, and vegetable oil or animal oil are mixed and shaken in proportion, and ultrasonically dissolved to obtain a progesterone oil solution, and the progesterone oil solution is filled in the soft capsule. , produced corpus luteum Ketone capsule; wherein, the non-polar solvent is used to dissolve the progesterone micropowder, the solubilizer is used to increase the solubility of progesterone, and the dissolution and bioavailability of progesterone in the progesterone capsule can be improved to improve the patient. The absorption of progesterone reduces the burden of excess progesterone metabolism in the liver; thus, it can overcome the defects of large dosage, low dissolution rate, low bioavailability and many adverse reactions in the prior art, so as to achieve a small dosage and dissolution rate. High, high bioavailability and few adverse reactions.

It should be noted that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art The technical solutions described in the foregoing embodiments may be modified, or some of the technical features may be equivalently replaced. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and scope of the invention are intended to be included within the scope of the invention.

The pharmaceutical properties of the progesterone capsules of the present invention were tested by experiments below.

Commercially available progesterone capsules, trade name: Qi Ning, manufacturer: Zhejiang Aisheng Pharmaceutical Co., Ltd.,

Batch number: 20080301

Specifications: lOOmg / grain

Experimental Example 1 : The stability of the progesterone capsule of the present invention was examined:

The progesterone capsules obtained in the above examples of the present invention were exposed to light at 3500 LX, and the temperatures were respectively room temperature, 40 ° C and 25 ° C, and the humidity was RH 92.5% and RH 75%, respectively, for 10 days. . The progesterone capsules of the present invention which are sealed and preserved are compared with the properties, the color of the contents, the fragmentation, the time limit of disintegration, the content determination and the chromatographic degradation products, and the comparison results show that the light and the temperature are different. The naked progesterone capsules of the present invention are substantially stable under humidity conditions.

In addition, the progesterone capsule of the present invention is sealed and packaged, and is accelerated for six months under the conditions of a temperature of 40 ° C and a humidity of RH of 75%, while being stored at room temperature for 24 months, and regularly according to a predetermined quality. The temperature standard was used to observe and measure the sample, and it was found that the traits of the sample were basically stable.

Experimental Example 2: The dissolution rate of the progesterone capsule of the present invention (Examples 1, 2, 4, 5, 7, each of which is 2 mg, 5 mg, 20 mg, 5 mg, 30 mg) in artificial gastric juice and commercially available The dissolution of progesterone capsules in artificial gastric juice was compared:

The progesterone capsules of the present invention and the commercially available progesterone capsules were respectively subjected to a dissolution test according to the second method of the Chinese Pharmacopoeia 2005 edition two appendix X dissolution method: the degassed artificial gastric juice 900ml The injection number is 1-6 in the container, and the artificial gastric juice can be maintained at 37 ± 0.5 ° C by heating; the contents of the progesterone capsule of the present invention and the commercially available progesterone glue are respectively weighed.丸(琪宁) The content of each sample is 0. 5g as the test solution, accurately weighed, injected into the corresponding six operating containers, immediately start the rotating container and start timing, the rotation speed is 50 rev / min, respectively at 30, 60 At 90, 120, 150, and 180 minutes, draw 20 ml of each solution from each of the 6 containers, and immediately fill in the same amount of white solution. The liquid is the artificial gastric juice of the same trait, and the aspirated solution is filtered through a 0. 45 μ πι microporous membrane, and the filtrate is measured by ultraviolet spectrophotometry. The absorbance is measured at a wavelength of 241 nm, and the absorption is based on progesterone. The coefficient is calculated as 540 and the percentage of dissolution per time is calculated. See the table below for the results. Here, the percentage by weight of progesterone in the progesterone capsules of the present invention (Examples 1, 2, 4, 5, 7, each of which is 2 mg, 5 mg, 20 mg, 5 mg, 30 mg) is 1.96%, respectively. 2. 44%, 2. 78%, 4. 76%, 2. 91%, the weight percentage of progesterone in the commercially available progesterone capsule is 37%, so, 0.5 g of the progesterone capsule of the present invention The progesterone containing ketones was 9.8 mg, 12.2 mg, 13.9 mg, 23.8 mg, 14. 55 mg, 0.5 g of commercially available progesterone capsules containing 185 mg of progesterone. Table 1: Percentage of dissolution of progesterone capsules containing 2 mg of progesterone in artificial gastric juice at various intervals (%)

Table 2: Percentage of dissolution of progesterone capsules containing 5 mg of progesterone in artificial gastric juice at various times (%) Container No. 30 min 60 min 90 min 120 min 150 min 180 min

1 9. 31 12. 91 23. 27 29. 02 35. 1 40. 06

2 7. 64 14. 28 22. 44 28. 75 37. 47 43. 2

3 8. 33 10. 18 20. 87 24. 08 35. 86 39. 22 4 7. 41 12. 75 23. 17 30. 76 41. 25 42. 36

5 10. 84 14. 89 19. 79 25. 63 34. 14 40. 18

6 9. 07 13. 14 20. 84 29. 91 37. 63 41. 97 Mean 7. 05 11. 83 20. 33 25. 86 37. 74 41. 33 Mean 8. 77 13. 03 21. 73 28. 03 36. 91 41. 17

SD 1. 26 1. 63 1. 43 2. 60 2. 52 1. 56 per 0. 5g

Progesterone

12. 2mg flat

Absolutely soluble

Quantity (mg) 1. 07 1. 59 2. 65 3. 42 4. 50 5. 02

Table 3: Percentage of dissolution of progesterone capsules containing 20mg of progesterone in artificial gastric juice at each time period (%) Container serial number 30min 60min 90min 120min 150min 180min

1 8. 31 12. 91 19. 27 28. 02 33. 1 42. 06

2 9. 64 13. 28 21. 44 30. 75 35. 47 39. 2

3 7. 33 10. 18 20. 87 23. 08 34. 86 38. 22

4 8. 41 12. 75 24. 17 30. 76 37. 25 41. 36

5 7. 84 13. 89 23. 79 27. 63 35. 14 40. 18

6 10. 07 14. 14 21. 84 29. 91 33. 63 42. 97 Mean 8. 60 12. 86 21. 90 28. 36 34. 91 40. 67

SD 1. 05 1. 42 1. 84 2. 91 1. 47 1. 79 per 0. 5g

Progesterone

13. 9mg flat

Absolutely soluble

Output (mg) 1. 20 1. 79 3. 04 3. 94 4. 85 5. 65 Table 4: Percentage of dissolution of progesterone capsules containing 5 mg of progesterone in artificial gastric juice at various intervals (%)

Table 5: Percentage of dissolution of progesterone capsules containing 30 mg of progesterone in artificial gastric juice at various intervals (%) Container No. 30 min 60 min 90 min 120 min 150 min 180 min

1 7. 31 10. 91 20. 27 29. 02 38. 1 42. 06

2 8. 64 13. 28 22. 44 30. 75 31. 47 38. 2

3 9. 33 12. 18 23. 87 29. 08 34. 86 40. 22

4 7. 41 13. 75 19. 17 28. 76 39. 25 41. 36

5 8. 84 13. 89 21. 79 27. 63 32. 14 41. 18

6 10. 07 14. 14 21. 84 25. 91 33. 63 39. 97 Mean 8. 60 13. 03 21. 56 28. 53 34. 91 40. 50

SD 1. 08 1. 25 1. 65 1. 62 3. 17 1. 36 Every 5. 5g

Progesterone

14. 55mg

Average absolute

Dissolution amount

(mg) 1. 25 1. 90 3. 14 4. 15 5. 08 5. 89 Table 6: Percentage of dissolution of progesterone capsules containing 100 mg of progesterone in artificial gastric juice at each time period (%)

As can be seen from Tables 1, 2, 3, 4, 5, and 6, in the artificial gastric juice, the dissolution rate of the progesterone capsule containing 2 mg, 5 mg, 20 mg, and 30 mg of the present invention is about 40% lower than that of the commercially available progesterone capsule. The degree is 1.58% high, and, over time, the progesterone capsules of the present invention are also eluted in a larger amount than the commercially available progesterone capsules. At 180 minutes, the dissolution rate of 5 mg of the progesterone capsule of the present invention is 41. 17 ± 1. 56%, containing the corpus luteum. The content of the content of the progesterone capsule is 1. 58 mg; 24%, the absolute dissolution of the content of the progesterone 100 mg is 1. 74 mg; visible In the artificial gastric juice, the absolute elution amount of the progesterone capsule of the present invention is 23 times that of the commercially available progesterone capsule, and it can be indicated that the progesterone capsule of the present invention is a highly effective preparation. Experimental Example 3: The dissolution rate of the progesterone capsule of the present invention in artificial intestinal juice was compared with the dissolution rate of commercially available progesterone capsules in artificial intestinal juice:

The dissolution rate of the progesterone capsule of the present invention and the commercially available progesterone capsule in the artificial intestinal juice was examined in accordance with the procedure of Experiment 2, and the results are shown in the following table.

Table 7: Percentage of dissolution of progesterone capsules containing progesterone 2mg in artificial intestinal fluid at various intervals (%) Container serial number 30min 60min 90min 120min 150min 180min

1 43. 12 50. 02 49. 73 51. 89 49. 1 49. 72

2 38. 45 43. 8 42. 51 49. 64 44. 13 46. 17

3 46. 59 49. 71 52. 76 58. 19 55. 42 57. 97

4 51. 27 53. 42 54. 75 57. 45 54. 57 54. 07

5 41. 98 51. 41 52. 4 57. 19 56. 48 54. 14

6 47. 78 49. 06 48. 62 53. 15 50. 19 52. 09 Mean 44. 87 49. 57 50. 13 54. 59 51. 65 52. 36

SD 4. 58 3. 22 4. 33 3. 51 4. 72 4. 07 Every 0. 5g

Progesterone

9. 8mg flat

Absolutely soluble

Output (mg) 4. 40 4. 86 4. 91 5. 35 5. 06 5. 13

Table 8: Percentage of dissolution of progesterone capsules containing progesterone 5mg in artificial intestinal fluid (%) Container serial number 30min 60min 90min 120min 150min 180min 1 44. 12 51. 02 49. 73 49. 89 50. 1 51. 72

2 38. 45 54. 8 52. 51 52. 64 52. 13 50. 17

3 46. 59 50. 71 48. 76 48. 19 50. 42 56. 97

4 39. 27 47. 42 53. 75 51. 45 53. 57 54. 07

5 49. 98 53. 41 50. 4 50. 19 56. 48 57. 14

6 49. 78 50. 06 48. 62 52. 15 59. 19 60. 09 Mean 44. 70 51. 24 50. 63 50. 75 53. 65 55. 03

SD 5. 02 2. 60 2. 08 1. 65 3. 58 3. 72 per 0. 5g

Progesterone

12. 2mg flat

Absolutely soluble

Output (mg) 5. 45 6. 25 6. 18 6. 19 6. 55 6. 71

Table 9: Percentage of dissolution of progesterone containing 20mg of progesterone capsules in artificial intestinal fluid (%) Container serial number 30min 60min 90min 120min 150min 180min

1 50. 12 52. 02 51. 73 52. 89 52. 1 52. 72

2 43. 45 51. 8 50. 51 53. 64 52. 13 52. 17

3 43. 59 51. 71 50. 76 52. 19 51. 42 50. 97

4 46. 27 49. 42 51. 75 54. 45 54. 57 53. 07

5 42. 98 52. 41 51. 4 52. 19 53. 48 55. 14

6 44. 78 53. 06 50. 62 56. 15 54. 19 50. 09 Mean 45. 20 51. 74 51. 13 53. 59 52. 98 52. 36

SD 2. 69 1. 24 0. 57 1. 53 1. 28 1. 76 per 0. 5g

Progesterone

13. 9mg flat

Absolutely soluble

Output (mg) 6. 28 7. 19 7. 11 7. 45 7. 36 7. 28 Table 10: Percentage of dissolution of progesterone capsules containing progesterone 5 mg in artificial intestinal fluid at various intervals (%)

Table ^1: Percentage of dissolution of progesterone capsules containing progesterone 30mg in artificial intestinal fluid (%) Container serial number 30min 60min 90min 120min 150min 180min

1 42. 12 48. 02 51. 73 53. 89 51. 1 51. 72

2 41. 45 50. 8 49. 51 52. 64 51. 13 51. 17

3 45. 59 47. 71 50. 76 53. 19 50. 42 51. 97

4 43. 27 48. 42 51. 75 55. 45 52. 57 52. 07

5 44. 98 52. 41 50. 4 53. 19 51. 48 52. 14

6 47. 78 51. 06 50. 62 54. 15 51. 19 51. 09 Mean 44. 20 49. 74 50. 80 53. 75 51. 32 51. 69

SD 2. 37 1. 94 0. 85 0. 99 0. 71 0. 46 Every 5. 5g

Progesterone

14. 55mg

Average absolute

Dissolution amount

(mg) 6. 43 7. 24 7. 39 7. 82 7. 47 7. 52

Table 12: Percentage of dissolution of commercially available progesterone capsules in artificial intestinal fluid (%)

, A ^, dodecyl seen from Table VI, seven, eight, nine, ten, in artificial intestinal juice, according to the present invention comprising 2mg, 5mg, 20m _g, 30mg progesterone capsules dissolution is about 50% greater than the commercial The progesterone capsules have a dissolution rate of 3.88%, and, over time, the progesterone capsules of the present invention are also eluted in a larger amount than the commercially available progesterone capsules. The dissolution of the content of the progesterone capsule of the present invention is 55. 03 ± 3. 72%, and the absolute amount of the content of the progesterone containing 12. 2 mg is 6. _71mg; commercially available progesterone capsules dissolution was 3. 88 ± 0. 67%, progesterone containing 100m _g absolute amount of elution of the content 3. _82mg; seen in artificial intestinal juice, the yellow of the invention The absolute elution amount of the ketone capsule is 14 times that of the commercially available progesterone capsule, and it can be shown that the progesterone capsule of the present invention is a highly effective preparation. Experimental Example 4: The bioequivalence test of the 10 mg progesterone capsule of the present invention and the commercially available 100 mg progesterone capsule was carried out as follows:

In this study, 6 males were used as test subjects, and the progesterone pill (specification lOmg) of the present invention and the commercially available progesterone pill (specification 100 mg) were respectively administered by single-dose fasting, and the plasma drug concentration was determined by radioimmunoassay at different times. Blood drug concentration-time data, the main pharmacokinetic parameters were obtained.

The Cmax of progesterone in the progesterone pill of the present invention is 2.73 ± 0. 77 (ng/ml), the Tmax is 1.5 (h), AUC (T48 is 42.38 ± 6.33 (ng/ml.h) The Cmax of the commercially available progesterone pellet is 2.78 ± 0.17 (ng/ml), the Tmax is 2. 5 ± 1 (h), and the AUCCT48 is 44. 42 ± 6. 12 (ng/ml. h) The statistical analysis of the above-mentioned main pharmacokinetic parameters and the evaluation of the bioequivalence showed that the average bioavailability of the progesterone capsules of the present invention is 95. 46 ± 12. 67%, there was no significant difference in Cmax, Tmax and AUCCT48 of progesterone between the two preparations (P>0.05). The 90% confidence of the AUC of the preparation of the present invention was limited to 76-132 of the commercially available preparation. Within the range of %, Cmax is in the range of 81% - 125%.

From this, it can be seen that the progesterone pellet of the present invention (specification lOmg) is bioequivalent to the human progesterone capsule (specification lOOmg) in the human body.

The pharmaceutical properties of the progesterone capsules having a high dissolution rate of the present invention are further illustrated by typical cases.

Case 1: Wang Jinhua, 47 years old, diagnosed as peri-menopausal without ovulation. After receiving the lutemg of the progesterone capsule of the present invention, the menstrual volume and the number of menstrual days returned to normal after 3 months of continuous use; the progesterone capsule lOmg of the present invention was added from the 17th day of menstruation, and the drug was discontinued after 10 days. The patient did not take other drugs before taking the progesterone capsule of the present invention, and did not take the estrogen drug when taking the progesterone capsule of the present invention.

Case 2: Chen Xiulian, 50 years old, menstruation nearly 4 months of future tide, B-ultrasound endometrium EN>13 hidden, diagnosed as menopause. The progesterone capsule of the present invention was treated with lOmg, and the endometrial exfoliation was continued after 10 days; after 3 months of the cycle treatment, the menstrual volume and the number of menstrual days returned to normal. The patient did not take other drugs before taking the progesterone capsule of the present invention, and did not take the estrogen drug when taking the progesterone capsule having the high dissolution rate of the present invention.

Case 3: Ye Lei, 32 years old, 3 months menstrual future tide, exclude pregnancy, diagnosed as amenorrhea. After receiving the lutemg of the progesterone capsule of the present invention, the menstrual volume and the number of menstrual days return to normal after 2 months of continuous use; the date is added from the 17th day of menstruation Invented 10 mg of progesterone capsules with high dissolution, and the drug was discontinued after 10 days. The patient does not take other drugs before taking the progesterone capsule with high dissolution rate of the present invention, and does not take the estrogen drug when taking the progesterone capsule of the present invention; the patient takes the progesterone capsule with high dissolution rate of the present invention. The time is about 3 months.

Case 4: Lu Xiaojie, 40 years old, diagnosed with premature ovarian failure. After receiving the 10 mg of progesterone capsule of the present invention, the menstrual volume and the number of menstrual days are normal after the second month of taking the progesterone capsule of the present invention; if the supplement is better, the treatment effect is better, and specific, in menstruation On the 5th day, take Jiajiale for 21 days; and take the progesterone capsule of the present invention on the 17th day of menstruation for 10 days. The treatment period is 3 months.

Clinically, the patient only needs to take 20mg of progesterone capsules per day to achieve an effective therapeutic dose, and it is convenient to take and has no adverse reactions.

Claims

Claim

A progesterone preparation composition comprising: a liquid solubilizing agent content having a pharmacologically active component and an outer wrapping material, characterized in that: the liquid solubilizing agent containing the pharmacologically active component is composed of a corpus luteum a progesterone oil solution prepared from a ketone and an auxiliary material; the auxiliary material is a non-polar solvent and a solubilizing agent, the non-polar solvent is a vegetable oil or/and an animal oil, and the solubilizing agent is lecithin or/and beeswax; The composition of the 1000-component preparation contains 2-30 g of progesterone, the solubilizer is 0-180 g, and the non-polar solvent is 75-1000 g.

The progesterone preparation composition according to claim 1, wherein the progesterone contains 5-20 g, the solubilizer is 0-100 g, and the non-polar solvent is 80-800 g per 1000 preparation compositions. .

The progesterone preparation composition according to Claim 2, which comprises 5 g of progesterone per kg of the composition of the preparation, a solubilizing agent of 0 to 50 g, and a nonpolar solvent of 80 to 200 g.

The progesterone preparation composition according to claim 2, which comprises 10 g of progesterone, a solubilizing agent of 0-80 g and a non-polar solvent of 100-500 g per 1000 parts of the preparation composition.

The progesterone preparation composition according to claim 2, which comprises 20 g of progesterone, a solubilizing agent of 0 to 100 g and a nonpolar solvent of 400 to 800 g per 1000 parts of the preparation composition.

6. The progesterone preparation composition according to claim 1, wherein the vegetable oil is peanut oil, soybean oil, rapeseed oil, corn oil, olive oil, sunflower oil, sesame oil, linseed oil, cottonseed oil, rice bran oil, One or more of coconut oil, camellia seed oil, canola oil, pepper oil, chili oil, and the like.

The progesterone preparation composition according to claim 1, wherein the animal oil is one or more of animal fat oils such as lard, tallow, sheep oil, chicken oil, and duck oil.

The progesterone preparation composition according to claim 1, wherein the lecithin is soybean lecithin or egg yolk lecithin.

The progesterone preparation composition according to claim 1, wherein the progesterone micropowder has a particle diameter of 90% of the progesterone micropowder of less than 10 μm.

The progesterone preparation composition according to claim 1, which is in the form of a soft capsule, a liquid capsule or a dropping pellet, and the outer wrapping material is gelatin, or gelatin and glycerin, or other clinically acceptable capsule outer wrapping. material.

11. The method for preparing a progesterone preparation composition according to claim 10, comprising: weighing the components of the contents in proportion, mixing and stirring to obtain a progesterone oil solution, and filling the progesterone oil solution on the soft capsule evenly. Or in hard capsules or pills.

12. The preparation method according to claim 11, wherein the mixing and mixing are performed by ultrasonic assisted dissolution.