CN1282459C - Progesterone capsule and preparing method thereof - Google Patents
Progesterone capsule and preparing method thereof Download PDFInfo
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- CN1282459C CN1282459C CN 02157710 CN02157710A CN1282459C CN 1282459 C CN1282459 C CN 1282459C CN 02157710 CN02157710 CN 02157710 CN 02157710 A CN02157710 A CN 02157710A CN 1282459 C CN1282459 C CN 1282459C
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- progesterone
- soft gelatin
- gelatin capsule
- tween
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Abstract
The present invention discloses a capsule preparation containing progesterone. Gelatin is coated outside a transparent liquid substance which is prepared from auxiliary materials, such as progesterone, solubilizing agents, surface active agents, etc., to be prepared into the capsule preparation. The progesterone capsules which are developed by the present invention can be used for oral application; compared with the progesterone injection which is sold in the market, the biological availability of the progesterone capsules is improved by 2.79 times, and the present invention has the characteristics of low taking dosage and high biological availability. The progesterone capsules can be used for various diseases or symptoms caused by lack of progestogen or inadequate luteal function.
Description
Technical field
The present invention relates to a kind of progesterone preparation.
Background technology
Progesterone, English name are progesterone, and its chemical name is pregnant steroid-4-alkene-3, the 20-diketone.It has the general action of progestogen, be used for menoxenia, as amenorrhea and dysfunctional uterine hemorrhage, the treatment of inadequate luteal function, threatened abortion and habitual abortion, premenstrualtension syndrome is used the effect of the simple estrogen of antagonism to inner membrance with the estrogen cycle.Also be used to improve the pregnancy rate of animal in addition.
But the Progesterone water solublity is very poor, oral post-absorption amount is few and very fast by the liver metabolism inactivation, therefore the dosage form of using clinically is injection, and is very inconvenient to patient especially life-time service person, and causes that easily the medicine local muscle composition that deposits causes lump pain etc.
Generally speaking, when water soluble drug was absorbed by digestive tract in the body, its absorbance and its dissolution velocity were directly proportional.Progesterone is a not soluble drug of water, and the absorption in digestive tract is very poor, and therefore at present domestic have only injection to use for injection clinically.In order to improve dissolution velocity, must increase its hydrophilic, therefore adopt HLB value high be the Progesterone soft gelatin capsule that surfactant and the good polyhydric alcohol of solubility property are made solution-type.
In view of above situation, developed the oral soft gelatin capsule UTROGESTAN (Utrogestan, patent No. US4196188) that gone on the market abroad and replaced injection.It has improved the oral bioavailability of Progesterone to a certain extent, but costs an arm and a leg, and content is because of being suspension, and taking dose is big, every day 200mg.
Summary of the invention
The technical issues that need to address of the present invention are to disclose a kind of new progesterone preparation, i.e. Progesterone solution-type soft gelatin capsule.This soft gelatin capsule is to be principal agent with the Progesterone, is equipped with the nonionic surfactant that improves the medicine stripping and other solubilizing agent and the high bioavailability soft gelatin capsule that makes.
This Progesterone soft gelatin capsule preparation of the present invention's development is a kind of soft gelatin capsule with pharmacologically active component liquid solution that includes.Soft gelatin capsule by include have pharmacologically active component solution and outer covering material is made according to common soft gelatin capsule preparation technology.
What include has pharmacologically active component solution, comprise pharmacologically active component Progesterone and adjuvant, used adjuvant comprises the solvent that is used for dissolving Progesterone such as PEG400, Macrogol 600, increases hydrophilic solubilizing agent of medicine such as surfactants such as Tween-20, Tween-80.
This Progesterone soft gelatin capsule that the present invention developed, by 1000 seed lac balls, contain Progesterone 2～15g, Tween-20, Tween-80 are 5～200g, and all the other are Polyethylene Glycol-400 or Polyethylene Glycol-600 or both mixture, for example, in per 1000 seed lac balls, contain Progesterone 5g, Tween-20 is 10g, and all the other are Polyethylene Glycol-400.
Preparation of the present invention is like this preparation: each component is mixed according to the above ratio, 20～80 ℃ of heating and constantly stirring down, treat the Progesterone dissolving after, get an amount of with the filling of revolving die formula soft gelatin capsule maker in soft gelatin capsule.
Stability to the Progesterone soft gelatin capsule that makes of the present invention is investigated:
This product removed outer package is directly exposed to place under illumination 3500LX, air at room temperature, 40 ℃, 25 ℃ RH92.5% and the RH75% condition each 10 days, carry out character, content color and luster, cracked property, disintegration, assay, chromatograph inspection catabolite etc. with the primary sample contrast, all basicly stable.Under the listing terms of packing, acceleration three months and room storage are 24 months under 40 ℃ of RH75% conditions, and regularly according to the accurate index observing mensuration of investigating of the matter temperature scale of working out, this product is basicly stable.
Progesterone is made into the solution A of PEG400 of the polysorbate 20 of 2% different proportion, B, C, D, E makes need testing solution, carry out the dissolution test by version Chinese Pharmacopoeia appendix XC dissolution method second method in 2000: measure the distilled water 300ml that handles through the degassing, inject in each process container, heat and make water remain on 37 ± 0-5 ℃, precision takes by weighing test liquid 2g, inject respectively in 6 process containers, startup rotation (50 rev/mins) immediately also picks up counting, during to 30 minutes, at the regulation sample point, draw an amount of solution, and filter through the 0.45um microporous filter membrane immediately, get subsequent filtrate and measure, calculate each stripping percentage rate, the results are shown in following table by spectrophotography:
The stripping percentage rate in water of Utrogestan soft gelatin capsule and each prescription (%, 30 minutes)
| The Utrogestan content | 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 |
By table as seen, Utrogestan micropowder soft gelatin capsule (content) was that dissolution is respectively 0.44 ± 0.17%, 14.20 ± 0.76%, 17.36 ± 1.86%, 24.89 ± 0.45%, 28.44 ± 2.78%, 57.83 ± 3.24% at 30 minutes with prescription A, B, C, D, E.Illustrate that prescription D is best.
Progesterone soft gelatin capsule of the present invention and An Qitan soft gelatin capsule are pressed two appendix X of Chinese Pharmacopoeia version in 2000 dissolution method three therapeutic methods of traditional Chinese medicine, with 0.1mol/L hydrochloric acid 250ml is solvent, rotating speed is that per minute 150 changes, operation in accordance with the law, in the time of 45 minutes, get subsequent filtrate and measure according to high performance liquid chromatography (appendix VD).The dissolution that calculates the two sees the following form.
The Progesterone soft gelatin capsule the results are shown in following table with " Utrogestan " soft gelatin capsule dissolution blank determination in 0.1mol/L HCl.
| Preparation | Dissolution (%) | Average (%)～SD | |||||
| Utrogestan | 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 |
Progesterone soft gelatin capsule and " Utrogestan " soft gelatin capsule absolute stripping quantity blank determination result in 0.1mol/L
| Preparation | Dissolution (%) | Average (%)～SD | |||||
| Utrogestan | 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 |
By table as seen, in 0.1mol/L HCl, the absolute stripping quantity of Progesterone soft gelatin capsule of the present invention is 5.66 times of import " An Qitan " soft gelatin capsule, and real is high-efficiency preparation.
Progesterone soft gelatin capsule animal relative bioavailability of the present invention experimental study:
With 6 of domesticated dogs is subjects, adopt consubstantiality cross matching method, irritate stomach gives Progesterone soft gelatin capsule of the present invention to the single intersection on an empty stomach respectively, contain Progesterone 100mg, or intramuscular injection Progesterone 100mg is a control formulation, adopt radioimmunoassay method different time blood plasma Chinese medicine concentration,, tried to achieve main pharmacokinetic parameter according to blood drug level-time data.
Result of calculation shows: the C of Progesterone in the Progesterone soft gelatin capsule of the present invention
MaxBe 247.31 ± 39.73 (ng/ml), T
MaxBe 0.88 ± 0.56 (h), t
1/2Be 2.98 ± 0.45 (h), AUC
0～10Be 901.74 ± 162.29 (ng/ml.h), AUC
0～∞Be 351.18 ± 30,74 (ng/ml, h).The C of Progesterone in the progesterone injection
MaxBe 119.06 ± 20.22 (ng/ml), T
MaxBe 0.29 ± 0.10 (h), t
1/2Be 2.04 ± 0.59 (h), AUC
0～10Be 335.69 ± 77.31 (ng/ml.h), AUC
0～∞Be 373.18 ± 87.82 (ng/ml.h).
Above-mentioned main pharmacokinetic parameter is carried out statistical analysis and evaluation of bioequivalence, and the result shows: the C of Progesterone between two kinds of preparations
Max, T
MaxAnd AUC
0～∞Significant significant difference (P (0.05) is all arranged; The average relative bioavailability of Progesterone is 279.60 ± 58.62% in the Progesterone soft gelatin capsule of the present invention, and 90% of its bioavailability parameter value crediblely is limited to 223.35～523.01%.Can find out thus Progesterone soft gelatin capsule of the present invention have taking dose low, absorb fast, blood drug level and the high characteristics of bioavailability.
The specific embodiment
Embodiment 1
A kind of soft gelatin capsule that contains Progesterone is made as outer covering material by Progesterone clear solution and gelatin that Progesterone and adjuvant are made.
Embodiment 2
Comprise solvent such as PEG400 or Macrogol 600 or both mixture that is used for dissolving Progesterone by embodiment 1 described adjuvant; Surfactant such as solubilizing agent such as polysorbate 20 or polyoxyethylene sorbitan monoleate.
Embodiment 3
Press embodiment 2 described soft gelatin capsules, in per 1000, contain Progesterone 5g, Tween-20 or polyoxyethylene sorbitan monoleate are 10g, and all the other are Polyethylene Glycol-400 or Macrogol 600 or both mixture.
Claims (2)
1. a soft gelatin capsule that includes Progesterone is made up of liquid solubilizing agent and the outer covering material with pharmacologically active component that include, it is characterized in that the liquid solubilizing agent with pharmacologically active component that includes, is the Progesterone solution of being made by Progesterone and adjuvant; Outer covering material is a gelatin, or gelatin, propylene glycol, or other acceptable clinically soft gelatin capsule outer covering materials;
Described adjuvant is PEG400 or Macrogol 600 and Tween-20 or Tween-80 surfactant;
Per 1000 seed lac ball meters contain Progesterone 2～15g, and Tween-20 or Tween-80 are 5～200g, and all the other are Polyethylene Glycol-400 or Polyethylene Glycol-600 or both mixture.
2. by the described soft gelatin capsule that contains Progesterone of claim 1, it is characterized in that per 1000 seed lac ball meters, contain Progesterone 5g, poly-Pyrusussuriensis cheese-20 or Tween-80 are 10g, and all the other are Polyethylene Glycol-400 or Macrogol 600 or both mixture.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02157710 CN1282459C (en) | 2002-12-24 | 2002-12-24 | Progesterone capsule and preparing method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 02157710 CN1282459C (en) | 2002-12-24 | 2002-12-24 | Progesterone capsule and preparing method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1509720A CN1509720A (en) | 2004-07-07 |
| CN1282459C true CN1282459C (en) | 2006-11-01 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 02157710 Expired - Fee Related CN1282459C (en) | 2002-12-24 | 2002-12-24 | Progesterone capsule and preparing method thereof |
Country Status (1)
| Country | Link |
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| CN (1) | CN1282459C (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101152186B (en) * | 2007-09-05 | 2011-07-06 | 杭州平和安康医药科技有限公司 | Progesterone injection and method for preparing the same |
| US9375437B2 (en) | 2010-06-18 | 2016-06-28 | Lipocine Inc. | Progesterone containing oral dosage forms and kits |
| US20110312928A1 (en) * | 2010-06-18 | 2011-12-22 | Lipocine Inc. | Progesterone Containing Oral Dosage Forms and Related Methods |
| US8951996B2 (en) | 2011-07-28 | 2015-02-10 | Lipocine Inc. | 17-hydroxyprogesterone ester-containing oral compositions and related methods |
| MX2017016823A (en) | 2015-06-22 | 2018-03-12 | Lipocine Inc | 17-hydroxyprogesterone ester-containing oral compositions and related methods. |
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- 2002-12-24 CN CN 02157710 patent/CN1282459C/en not_active Expired - Fee Related
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