CN112336699A - Progesterone vaginal slow-release soft capsule and its preparation method - Google Patents

Progesterone vaginal slow-release soft capsule and its preparation method Download PDF

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Publication number
CN112336699A
CN112336699A CN201910735005.1A CN201910735005A CN112336699A CN 112336699 A CN112336699 A CN 112336699A CN 201910735005 A CN201910735005 A CN 201910735005A CN 112336699 A CN112336699 A CN 112336699A
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progesterone
soft capsule
suspension
solution
vaginal
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孙军娣
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Nanjing Kening Testing Technology Co ltd
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Nanjing Kening Testing Technology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants

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  • Pharmacology & Pharmacy (AREA)
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  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
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  • Reproductive Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Endocrinology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gynecology & Obstetrics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pregnancy & Childbirth (AREA)
  • Urology & Nephrology (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention relates to a progesterone vaginal soft capsule for treating threatened abortion, which utilizes a novel surfactant of polyethylene glycol glyceryl stearate to enhance the stability of progesterone vaginal suspension, and then wraps the vaginal suspension in a soft capsule shell, thereby having the advantages of avoiding first pass effect, improving bioavailability, increasing the accuracy of administration dosage and facilitating administration.

Description

Progesterone vaginal slow-release soft capsule and its preparation method
Technical Field
The invention belongs to the technical field of pharmacy, and particularly relates to a suspension progesterone vaginal soft capsule and a preparation method thereof.
Background
Progesterone, a natural progestogen secreted by the ovarian corpus luteum, also known as progesterone and gestagen, has significant morphological effects on the estrogen-stimulated endometrium in vivo and is essential for maintaining pregnancy. In the clinic, it is mainly used for the treatment of menstrual disorders such as amenorrhea endometrial hemorrhage, corpus luteum insufficiency, threatened abortion and habitual abortion, premenstrual tension syndrome, etc., and in Hormone Replacement Therapy (HRT) in combination with estrogens to counteract the effects of simple estrogens on the endometrium.
Currently, the commonly used pharmaceutical dosage forms of progesterone include: capsules, soft capsules, gels, suppositories, injections and the like, and the progesterone oral preparation is rapidly destroyed in the liver and the gastrointestinal tract, has low bioavailability, only a small amount of medicine acts on the uterus, and cannot achieve ideal treatment effect, so the injection administration and the local administration of the vagina become common administration modes. However, after injection administration, the blood concentration fluctuation is large, muscle hardening and other toxic and side effects are easily caused, and vaginal local administration becomes an optimal way for treating women threatened abortion.
Suppositories and gels are currently the predominant form of vaginal administration of progesterone. The suppository releases the medicine through the matrix softened by body temperature, and is easy to leak if the suppository is melted too fast and fall off if the suppository is melted too slowly. The gel is a thin semisolid, has certain fluidity, and is easy to flow out along with vaginal secretion after administration, so that the curative effect is reduced.
Fats and fatty acids are currently of increasing interest as carriers for drug delivery systems. The macrogol glyceride stearate is a semi-solid waxy medicinal auxiliary material developed in the French Jiafa game, is a surfactant formed by mixing mono-glyceride, di-glyceride, triglyceride and polyethylene glycol fatty acid ester, has different melting points (33-65 ℃) and HLB value ranges, and can obtain different drug release speeds by mixing different types of macrogol glyceride stearate. Wherein the stearic acid polyethylene glycol glyceride 50/13 (Gelucire 50/13) has high HLB value and low density, and can promote the release of hydrophobic progesterone from hydrophilic matrix through the functions of pore diffusion and matrix erosion, and improve the dispersibility of the medicament in the suspension. Gelucire 50/13 also has self-emulsifying effect, and can form fine emulsion when contacting vaginal fluid, promote insoluble but extremely fine drug particles to be uniformly dispersed in release medium, increase drug solubility, and improve bioavailability.
Aiming at the problems, the invention provides a novel progesterone vaginal soft capsule and a preparation method thereof, which is characterized in that after progesterone is micronized to a certain particle size, a suspension is prepared by means of a novel surfactant of polyethylene glycol glyceryl stearate to increase the dissolution rate and the membrane penetration rate of the progesterone and simultaneously improve the stability. The progesterone suspension is wrapped in soft capsules to facilitate vaginal administration, and the accuracy of administration dosage is improved.
Disclosure of Invention
The invention relates to a suspension progesterone soft capsule for vaginal administration and a preparation method thereof.
The invention utilizes the novel cosurfactant, namely the polyethylene glycol stearate (Gelucire 50/13), to increase the solubility of the progesterone and improve the dissolution rate and the membrane permeation rate. Gelucire 50/13 is a waxy amphiphilic material with an HLB value of up to 13, and by virtue of its high hydrophilicity and low density, it promotes the release of hydrophobic progesterone from hydrophilic matrices by interstitial diffusion and matrix erosion, while improving the dispersibility of the drug in suspension. The self-emulsifying action of Gelucire 50/13, when in contact with vaginal fluid, forms a fine emulsion that promotes uniform dispersion of insoluble but very fine drug particles in the delivery medium, increasing drug solubility and permeation rates.
Specifically, the technology of the invention is realized as follows:
a progesterone soft capsule for vaginal administration is prepared through preparing the suspension of progesterone, soybean oil, polyethanediol stearate, sorbic acid and beeswax, and sealing in soft capsule shell.
The specification of the suspension type progesterone soft capsule comprises but is not limited to 100mg-200 mg.
Further, the particle size of the progesterone is controlled to be 4-20 μm, and the micronization mode includes but is not limited to a ball mill, a fluid energy mill and a jet mill;
furthermore, the stearic acid macrogol glyceride accounts for 1-2% of the weight of the soft capsule;
the preparation process of the suspension type progesterone vaginal soft capsule comprises the following three steps: micronizing a progesterone raw material, preparing a progesterone suspension, and filling the progesterone suspension into a soft capsule shell.
The preparation method of the progesterone suspension comprises the following specific steps:
step a: preparation of solution a: sequentially adding sorbic acid and beeswax into 70% soybean oil according to the formula amount, heating to 50 ℃, and stirring until the sorbic acid and the beeswax are completely dissolved;
step b: preparation of solution B: heating and melting the stearic acid polyethylene glycol glyceride, adding 30% of soybean oil according to the prescription amount, and uniformly stirring. Adding micronized progesterone raw material into the mixture, and quickly stirring to uniformly disperse the progesterone raw material;
step c: preparation of progesterone suspension: adding solution A into solution B, homogenizing at 3000-4500 rpm under high pressure for 10-15min to obtain uniform progesterone suspension, and adjusting pH to 3-5.
Step d: preparing progesterone vaginal soft capsules: pressing the progesterone suspension and soft capsule gel solution with a pill press to obtain soft capsule.
The following experimental examples and results are provided for further description of the features of the present invention and are not intended to limit the present invention.
1. In order to fully illustrate the dispersing ability of Gelucire 50/13 to progesterone in the present invention, we compared the precipitation ratios of progesterone raw materials before and after adding Tween 80, poloxamer 188 and PEG-glyceryl stearate, at different time points (0 day, 5 days, 10 days, 30 days and 60 days), and the results are shown in Table 1.
2. In order to fully illustrate the sustained release effect of Gelucire 50/13 on progesterone in the present invention, the in vitro release of progesterone in 0.25% sodium dodecyl sulfate release medium was compared before and after adding Tween 80, poloxamer 188, and glyceryl polyethylene glycol stearate to the progesterone, and the results are shown in Table 2.
Detailed Description
The present invention is further described with reference to the following examples, which should not be construed as limiting the invention thereto.
EXAMPLE 1 progesterone suspension Soft capsules (size: 100 mg)
Prescription dose (g)
Progesterone 100
Soybean oil 750
Gelucire 50/13 10
Sorbic acid 2
Beeswax 35.9
Making into 1000 pieces
(1) 525g of soybean oil is taken, sorbic acid and beeswax are sequentially added, the mixture is heated to 50 ℃, and the mixture is stirred until the mixture is completely dissolved to be used as A liquid for standby.
(2) Adding Gelucire 50/13After hot melting, 225g of soybean oil in the prescribed amount was added and stirred well. Adding air-micronized progesterone (D)90=7.56 μm), disperse progesterone evenly by rapid stirring, and prepare solution B for later use.
(3) Adding solution A into solution B, homogenizing at 3500rpm under high pressure for 15min to obtain uniform progesterone suspension, and measuring pH to 3.7. Then pressing the progesterone suspension and the soft capsule glue solution by a pill press to prepare the soft capsule.
EXAMPLE 2 progesterone suspension Soft capsules (size: 150 mg)
Prescription dose (g)
Progesterone 150
Soybean oil 800
Gelucire 50/13 15
Sorbic acid 2.2
Beeswax 50.9
Making into 1000 pieces
(1) 560g of soybean oil is taken, sorbic acid and beeswax are sequentially added, the mixture is heated to 50 ℃, and the mixture is stirred until the mixture is completely dissolved to be used as solution A for later use.
(2) Gelucire 50/13 was heated to melt, and then 240g of soybean oil was added and stirred well. Adding air-micronized progesterone (D)90=12.33 μm), and the progesterone is dispersed uniformly by rapid stirring to prepare a solution B for later use.
(3) Adding solution A into solution B, homogenizing at 3500rpm under high pressure for 15min to obtain uniform progesterone suspension, and adjusting pH to 4.5 with sodium hydroxide solution. Then pressing the progesterone suspension and the soft capsule glue solution by a pill press to prepare the soft capsule.
EXAMPLE 3 progesterone suspension Soft capsules (size: 200 mg)
Prescription dose (g)
Progesterone 200
Soybean oil 850
Gelucire 50/13 20
Sorbic acid 2.2
Beeswax 68.4
Making into 1000 pieces
(1) 595g of soybean oil are taken, sorbic acid and beeswax are added in sequence, the mixture is heated to 50 ℃, and the mixture is stirred until the mixture is completely dissolved to be used as liquid A for standby.
(2) Gelucire 50/13 was heated to melt, and 255g of soybean oil was added and stirred well. Adding air-micronized progesterone (D)90=16.38 μm), and the progesterone is dispersed uniformly by rapid stirring to prepare a solution B for later use.
(3) Adding solution A into solution B, homogenizing at 3500rpm under high pressure for 15min to obtain uniform progesterone suspension, and adjusting pH to 4.5 with sodium hydroxide solution. Then pressing the progesterone suspension and the soft capsule glue solution by a pill press to prepare the soft capsule.
EXAMPLE 4 progesterone suspension Soft capsules (size: 200 mg)
Prescription dose (g)
Progesterone 200
Soybean oil 850
Tween 8020
Sorbic acid 2.2
Beeswax 68.4
Making into 1000 pieces
(1) 595g of soybean oil are taken, sorbic acid and beeswax are added in sequence, the mixture is heated to 50 ℃, and the mixture is stirred until the mixture is completely dissolved to be used as liquid A for standby.
(2) Adding tween 80 into 255g soybean oil, stirring to dissolve, adding progesterone (D) micronized by air flow90=14.25 μm), and rapidly stirring to uniformly disperse progesterone to prepare a solution B for later use.
(3) Adding solution A into solution B, homogenizing at 3500rpm under high pressure for 15min to obtain uniform progesterone suspension, and adjusting pH to 4.5 with sodium hydroxide solution. Then pressing the progesterone suspension and the soft capsule glue solution by a pill press to prepare the soft capsule.
EXAMPLE 5 progesterone suspension Soft capsules (size: 200 mg)
Prescription dose (g)
Progesterone 200
Soybean oil 850
Poloxamer 18820
Sorbic acid 2.2
Beeswax 68.4
Making into 1000 pieces
(1) 595g of soybean oil are taken, sorbic acid and beeswax are added in sequence, the mixture is heated to 50 ℃, and the mixture is stirred until the mixture is completely dissolved to be used as liquid A for standby.
(2) Adding poloxamer 188 into 255g soybean oil, stirring to dissolve, adding progesterone (D) micronized by airflow90=16.23 μm), and the progesterone is dispersed uniformly by rapid stirring to prepare a solution B for later use.
(3) Adding solution A into solution B, homogenizing at 3500rpm under high pressure for 15min to obtain uniform progesterone suspension, and adjusting pH to 4.5 with sodium hydroxide solution. Then pressing the progesterone suspension and the soft capsule glue solution by a pill press to prepare the soft capsule.
Example 6 suspension Effect of Progesterone suspension
The contents (suspensions) of progesterone vaginal soft capsules of the same specification prepared by different surfactants were examined for sedimentation volume ratio at 0 day, 5 days, 10 days, 30 days, 60 days as in examples 3-5, and the results are shown in table 1. As can be seen from the experimental results in Table 1, the suspension property of the progesterone is remarkably improved by adopting Gelucire 50/13 as a suspending agent; meanwhile, after the progesterone raw material is micronized, the suspension effect of Gelucire 50/13 on progesterone is better than that of progesterone which is not micronized, and the concentration requirement of 200mg progesterone vaginal soft capsules can be met.
TABLE 1 comparison of sedimentation volume ratios for different formulations
Figure DEST_PATH_IMAGE001
Example 7 in vitro Release of progesterone Soft capsules
The in vitro release of progesterone vaginal soft capsules of the same size prepared with different surfactants in a 0.25% sodium lauryl sulfate release medium was examined as in examples 3-5, the results of which are shown in table 2. The experimental results in table 2 show that the slow release of progesterone in vitro vaginal soft capsules for 48 hours can be realized by using Gelucire 50/13 as a suspending agent and a surfactant, and compared with Tween 80, poloxamer 188 and Gelucire 50/13, the slow release soft capsules for progesterone are more complete in release. Meanwhile, after the progesterone raw material is micronized, the slow release effect of the progesterone raw material is obviously superior to that of the raw material which is not processed.
TABLE 2 comparison of in vitro Release for different formulations
Figure 122647DEST_PATH_IMAGE002

Claims (7)

1. The invention provides a progesterone vaginal soft capsule and a preparation method thereof, wherein the content of the soft capsule is progesterone suspension, and the progesterone vaginal soft capsule is characterized in that a suspending agent of the progesterone suspension is polyethylene glycol glyceryl stearate.
2. The progesterone vaginal soft capsule of claim 1, wherein the excipients used in the formulation comprise soybean oil, glyceryl polyethylene glycol stearate, sorbic acid, beeswax.
3. The progesterone vaginal soft capsule according to claim 1, characterized in that it uses polyoxylglyceride stearate as suspending agent, preferably in an amount of 1-2% (by weight).
4. The progesterone vaginal soft capsule according to claim 1, characterized in that the progesterone soft capsule is in a size of 100mg to 200 mg.
5. The process for the preparation of vaginal soft capsules of progesterone according to any one of claims 1 to 4, characterized by the following:
(1) adding 70% of soybean oil, sorbic acid and beeswax according to the prescription amount in sequence, heating to 50 ℃, and stirring until the mixture is completely dissolved to serve as liquid A for later use;
(2) heating and melting stearic acid polyethylene glycol glyceride, adding 30% of soybean oil according to the prescription amount, and uniformly stirring; adding micronized progesterone raw material into the solution, and rapidly stirring to uniformly disperse the progesterone raw material to obtain solution B for later use;
(3) adding solution A into solution B, homogenizing under high pressure to obtain uniformly dispersed progesterone suspension, adjusting pH to 3-5, and making into soft capsule with the progesterone suspension and soft capsule gel solution by a pill press.
6. The progesterone vaginal soft capsule according to claim 5, wherein the progesterone material is micronized by a suitable process, the progesterone preferably having a particle size of 4 μm to 20 μm.
7. The process for preparing progesterone vaginal soft capsules according to claim 5, characterized in that the stirring parameters are comprised between 100rpm and 200 rpm; the homogenization parameters are 3000rpm-4500 rpm.
CN201910735005.1A 2019-08-09 2019-08-09 Progesterone vaginal slow-release soft capsule and its preparation method Pending CN112336699A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113908114A (en) * 2021-10-29 2022-01-11 宁波第二激素厂 Flugesterone acetate vaginal sponge
CN113975226A (en) * 2021-10-29 2022-01-28 宁波第二激素厂 Preparation method of fluoprogesterone acetate vaginal sponge

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015148952A1 (en) * 2014-03-28 2015-10-01 Therapeuticsmd, Inc. Progesterone formulations

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015148952A1 (en) * 2014-03-28 2015-10-01 Therapeuticsmd, Inc. Progesterone formulations

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113908114A (en) * 2021-10-29 2022-01-11 宁波第二激素厂 Flugesterone acetate vaginal sponge
CN113975226A (en) * 2021-10-29 2022-01-28 宁波第二激素厂 Preparation method of fluoprogesterone acetate vaginal sponge
CN113975226B (en) * 2021-10-29 2024-02-09 宁波第二激素厂 Preparation method of fluogesterone acetate vaginal sponge
CN113908114B (en) * 2021-10-29 2024-02-09 宁波第二激素厂 Fluogesterone acetate vaginal sponge

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Application publication date: 20210209