CN102415995A - Oversaturated self-microemulsified progesterone composition and preparation method of same - Google Patents
Oversaturated self-microemulsified progesterone composition and preparation method of same Download PDFInfo
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- CN102415995A CN102415995A CN2011104086493A CN201110408649A CN102415995A CN 102415995 A CN102415995 A CN 102415995A CN 2011104086493 A CN2011104086493 A CN 2011104086493A CN 201110408649 A CN201110408649 A CN 201110408649A CN 102415995 A CN102415995 A CN 102415995A
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- progesterone
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- microemulsion
- emulsion composition
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- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 title claims abstract description 524
- 239000000186 progesterone Substances 0.000 title claims abstract description 261
- 229960003387 progesterone Drugs 0.000 title claims abstract description 261
- 239000000203 mixture Substances 0.000 title claims abstract description 81
- 238000002360 preparation method Methods 0.000 title abstract description 27
- 239000004530 micro-emulsion Substances 0.000 claims abstract description 71
- 238000010790 dilution Methods 0.000 claims abstract description 27
- 239000012895 dilution Substances 0.000 claims abstract description 27
- 239000010773 plant oil Substances 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000003381 stabilizer Substances 0.000 claims abstract description 13
- 239000007788 liquid Substances 0.000 claims abstract description 8
- 238000002156 mixing Methods 0.000 claims abstract description 5
- 238000009210 therapy by ultrasound Methods 0.000 claims abstract 3
- 239000000839 emulsion Substances 0.000 claims description 71
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 42
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 35
- -1 Polyoxyethylene Polymers 0.000 claims description 35
- 239000002245 particle Substances 0.000 claims description 33
- 239000002202 Polyethylene glycol Substances 0.000 claims description 23
- 229920001223 polyethylene glycol Polymers 0.000 claims description 23
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 21
- 125000005456 glyceride group Chemical group 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- 239000003921 oil Substances 0.000 claims description 20
- 239000004359 castor oil Substances 0.000 claims description 19
- 235000019438 castor oil Nutrition 0.000 claims description 19
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 19
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical class CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 claims description 16
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 16
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- WECGLUPZRHILCT-GSNKCQISSA-N 1-linoleoyl-sn-glycerol Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC[C@@H](O)CO WECGLUPZRHILCT-GSNKCQISSA-N 0.000 claims description 14
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- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 8
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 8
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- FMMOOAYVCKXGMF-MURFETPASA-N ethyl linoleate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OCC FMMOOAYVCKXGMF-MURFETPASA-N 0.000 claims description 6
- 229940031016 ethyl linoleate Drugs 0.000 claims description 6
- FMMOOAYVCKXGMF-UHFFFAOYSA-N linoleic acid ethyl ester Natural products CCCCCC=CCC=CCCCCCCCC(=O)OCC FMMOOAYVCKXGMF-UHFFFAOYSA-N 0.000 claims description 6
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
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- ZBCATMYQYDCTIZ-UHFFFAOYSA-N 4-methylcatechol Chemical compound CC1=CC=C(O)C(O)=C1 ZBCATMYQYDCTIZ-UHFFFAOYSA-N 0.000 claims description 2
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention provides an oversaturated self-microemulsified progesterone composition. The oversaturated self-microemulsified progesterone composition consists of progesterone, non-natural plant oil, emulsifier, assistant emulsifier, stabilizer and the like. A preparation method of the oversaturated self-microemulsified progesterone composition comprises the following steps of: uniformly mixing the non-natural plant oil and the assistant emulsifier; dissolving the progesterone in the mixed liquid after being subjected to ultrasonic treatment; and adding the emulsifier into the mixture, and adding to dissolve or suspend the stabilizer in the mixture to obtain the composition. In the invention, as the progesterone is solubilized in 10-90nm oil-in-water microemulsion, dissolubility and dissolution rate of the progesterone in gastrointestinal fluid are increased; the microemulsion which is formed after oral administration envelops the progesterone in the non-natural plant oil and a surfactant layer so as to prevent the progesterone from being degraded by acid and enzyme in a gastrointestinal tract; and the stabilizer can be used for inhibiting progesterone crystals from precipitation during the dilution of the microemulsion to form oversaturated progesterone solution, so that more progesterone can be absorbed. The oversaturated self-microemulsified progesterone composition has the characteristics of low viscosity, stability in quality, high bioavailability, low toxicity, less side effect, short preparation time, low energy consumption and the like.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, relate to Progesterone supersaturated self-emulsion composition of a kind of high oral administration biaavailability and preparation method thereof.
Background technology
Progesterone (English name progesterone; Chemistry pregnant steroid by name-4-alkene-3; The 20-diketone) is natural progestogen; Have pregnancy hormone like-effect, be widely used in treating threatened abortion, habitual abortion, artificial insemination after, disease or symptom due to progestogen such as infertile, premenstrualtension syndrome, anovulatory functional bleeding, the amenorrhea of anovulation type, endometrium hyperplasia, adenocarcinoma of endometrium, endometriosis and climacteric syndrome or the inadequate luteal function.At hormonal supplementation therapy (hormone replacement therapy; HRT) in; Give and the estrogenic while, must give simultaneously and progestogen continuously or at delayed menstrual cycle for a long time, to avoid endometrial hyperplasia; Reduction is suffered from the risk of carcinoma of endometrium because of single with the caused postmenopausal women of estrogen, and prevention of osteoporosis and periodontal better.And Progesterone is the composition that exists in the body, side effect minimum in the progestogens medicine, and therefore, the oral natural progesterone preparation has great clinical demand in HRT.
Progesterone is very low because of dissolubility, and absorption difference in the body, and have strong first pass effect after oral can a plurality of in vivo tissue metabolisms, and the half-life is extremely lacked (being merely several minutes), and bioavailability is very low and the patient individual difference is bigger, generally uses as intramuscular injection clinically.But Progesterone often needs long term administration in treatment, intramuscular administration has brought great inconvenience to the patient, and the spindle agent causes malabsorption to local muscular irritation easily after multiple injection; Untoward reaction such as drug accumulation is prone to cause scleroma, redness, itches, pain; Especially local scleroma is more common, brings certain misery to the patient, and long term administration also can make the medicine-feeding part amyotrophy; Patient's compliance is poor, has limited Progesterone in clinical extensive use.
Synthetic progestin class medicine like norethindrone, medroxyprogestetone acetate, norgestrel etc., is difficult for metabolism in vivo, and bioavailability significantly improves than natural progesterone, in clinical, is extensively adopted.But synthetic progestin has androgen-like action; Use the back and be prone to produce fluid retention; And cause patient's high density lipoprotein (HDL) to change, disturb carbohydrate metabolism, the arterial wall tissue morphology is changed, and there are side effect such as headache, mood change, fetus are manlike, teratogenesis.Up to now, the artificial synthetic progestogen of neither one can be brought into play and the identical hormone effect of natural progesterone, and the oral progestogen of synthetic can not replace Progesterone fully.
The U.S. Pat 4196188 oral soft gelatin capsule of a kind of micronization Progesterone of having reported for work, domestic Aisheng Pharmaceutical Co., Ltd., Zhejiang micronization Progesterone soft gelatin capsule (micronization Progesterone, specification 100mg/ grain) that also gone on the market; The micronization Progesterone is through reducing the Progesterone particle diameter; Increased the absorption after Progesterone is oral, bioavailability is increased, but micronization Progesterone medication individual variation is bigger; And can not avoid Progesterone metabolism in vivo; So overcome the absorption difference and the metabolic problems of Progesterone, Progesterone is applied to oral administration, become the key issue in the Progesterone application.
Chinese patent 200710049940.X discloses a kind of submicron emulsion (fat milk) progesterone injection; This injection contains 45.5% moisture at least; The crude vegetal that adopts is difficult to by emulsifying; The emulsion particle diameter that forms is bigger, and submicron emulsion is thermodynamic unstable system, causes progesterone injection unstable easily; And the drug administration by injection untoward reaction is many, carry inconvenience, and patient's compliance is poor; In addition, when preparing the submicron emulsion progesterone injection, this method also needs external force actings such as high pressure homogenizer, preparation technology's more complicated.
Summary of the invention
One of the object of the invention provides a kind of Progesterone supersaturated self-emulsion composition.
Another object of the present invention provides a kind of method for preparing of Progesterone supersaturated self-emulsion composition.
Progesterone supersaturated self-emulsion composition of the present invention, form by weight percentage by following composition:
Progesterone 0.5%-8%
Non-natural plant oil 10%-55%
Polyoxyethylene castor oil or polyoxyethylene hydrogenated Oleum Ricini 15%-40%
Polyoxyethylene sorbitan monoleate or sad capric acid polyethyleneglycol glyceride 5%-20%
Co-emulsifier 5%-30%
Stabilizing agent 0.1-5%.
Wherein, Described non-natural plant grease separation is from Capterx300, Captex355 (U.S. Abitec Company products), GTCC (Lanxi, Zhejiang thing beautifies worker's company limited product), Labrafac CC (French Jia Fasai (Gattefoss é) Company products), MCT oil (Chinese Tieling Beiya Medical Oil Co., Ltd. product), Miglyol 812N (German husky rope (Sasol) Company products), NeobeeM5 (U.S. Si Taipan (Stepan) Company products), Labrafac lipophile WL 1349 MCT Oils such as (French Jia Fasai (Gattefoss é) Company products); Glyceryl linoleate; Ethyl linoleate, ethyl oleate a kind of or several kinds mixture wherein.Be preferably ethyl oleate, MCT Oil, glyceryl linoleate, Ethyl linoleate, MCT Oil and glyceryl linoleate or oleic mixture; Described polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, sad capric acid polyethyleneglycol glyceride, polyoxyethylene sorbitan monoleate are emulsifying agent, and the ratio of polyoxyethylene castor oil or polyoxyethylene hydrogenated Oleum Ricini and sad capric acid polyethyleneglycol glyceride or polyoxyethylene sorbitan monoleate is 1:1～5:1; Described co-emulsifier is selected from PEG400, TC (Transcutol P, French Jia Fasai (Gattefoss é) Company products), isopropyl alcohol, ethanol, 1,2-propylene glycol wherein a kind of or several kinds mixture wherein; The mass ratio of emulsifying agent and co-emulsifier is 1:1-4:1; Described stabilizing agent is selected from one or several in polyvinylpyrrolidone, hypromellose, dextran, arabic gum, gelatin, the Polyethylene Glycol of molecular weight more than 1000.
Progesterone supersaturated self-emulsion composition of the present invention, fill a prescription preferably and form by weight percentage by following composition:
Progesterone 8.0%
MCT Oil 18.5%
Glyceryl linoleate 18.5%
Polyoxyethylene castor oil 30.0%
Sad capric acid polyethyleneglycol glyceride 6.0%
TC 18.0%
Hypromellose 1.0%.
The method for preparing of Progesterone supersaturated self-emulsion composition of the present invention may further comprise the steps:
(1) under the room temperature, non-natural plant oil and co-emulsifier mixing with recipe quantity stir; Described non-natural plant oil preferred oil acetoacetic ester, MCT Oil, glyceryl linoleate; Ethyl linoleate, MCT Oil and glyceryl linoleate or oleic mixture, the preferred TC of described co-emulsifier; PEG400, isopropyl alcohol;
(2) be that 30 ℃-40 ℃, power are under the condition of 40w with the Progesterone of recipe quantity in temperature; Carry out supersound process 30min with ultrasonic cleaner (the KQ-250DB type ultrasonic cleaner that Kunshan Ultrasonic Instruments Co., Ltd. produces); Progesterone is dissolved in the time of 30 ℃-40 ℃ in the mixed liquor of non-natural plant oil and co-emulsifier of step (1) very soon; With among the patent 200710049940.X preparation technology 60 ℃-70 ℃ compare, energy consumption reduces highly significant;
(3) mixed liquor with step (2) is cooled to room temperature; The polyoxyethylene castor oil or polyoxyethylene hydrogenated Oleum Ricini and sad capric acid polyethyleneglycol glyceride or the polyoxyethylene sorbitan monoleate that add recipe quantity use magnetic stirrer even, add stabilizing agent dissolving or suspendible then and wherein promptly get the Progesterone supersaturated self-emulsion composition; When the water with arbitrary proportion is diluted to microemulsion; Its particle size distribution is between 10-90nm, and the microemulsion that obtains after dilution particle diameter in 8 hours does not have significance to be changed, and the present invention is dissolved in Progesterone in the mixed liquor of non-natural plant oil and co-emulsifier; Add polyoxyethylene castor oil or polyoxyethylene hydrogenated Oleum Ricini, sad capric acid polyethyleneglycol glyceride or polyoxyethylene sorbitan monoleate and stabilizing agent again; Liquid in the oral post-absorption gastrointestinal tract, at polyoxyethylene castor oil or polyoxyethylene hydrogenated Oleum Ricini, sad capric acid polyethyleneglycol glyceride or polyoxyethylene sorbitan monoleate and help co-emulsifier to reduce under the effect of oil water interfacial tension, self emulsifying forms water oil-packaging type micro-emulsion liquid; At this moment; Non-natural plant oil (inner phase or decentralized photo) is scattered in the water (foreign minister or continuous phase) with liquid pearl form, and amphiphilic emulsifying agent and co-emulsifier are distributed on the oil-water interfaces, non-natural plant oil and table active agent layer in Progesterone is dissolved in; This structure of microemulsion makes it to have following pharmaceutics characteristic: the dissolubility that has 1. improved Progesterone; The microemulsion oil droplet that oral back forms 10-90nm has bigger interfacial area, simultaneously because its low surface tension, makes the direct and gastrointestinal epithelial cells contacting of Progesterone easily through the hydrated sheath of gastrointestinal wall; Increased permeability, promoted the absorption of Progesterone intestinal epithelial cell; 2. in effectively Progesterone being encapsulated in non-natural plant oil and the surfactant layer, thereby the protection Progesterone avoids the degraded of acid and enzyme in the gastrointestinal tract; 3. can absorb through the intestinal lymphatic vessel behind the microemulsion oral, overcome the Progesterone liver first-pass effect;
stabilizing agent suppresses the Progesterone crystallization and separates out in dilution; Increase the Progesterone saturation solubility; Form the Progesterone supersaturated solution, can further increase the absorption of Progesterone;
microemulsion administration can reduce the peak/paddy ratio of drug-time curve, the medication individual variation of dwindling Progesterone;
(4) give medically acceptable carrier with the Progesterone self-emulsion composition; Adopt method well known in the art to be prepared into tablet, capsule, soft capsule, oral liquid, oral gel or granule etc.; Described medical science carrier is meant pharmaceutical carrier conventional in the pharmaceutical field; As when processing oral liquid, can add diluent, excipient such as water etc.; When processing granule, can add adsorbent such as mannitol, citric acid, microcrystalline Cellulose etc., when processing tablet, can add binding agent, like polyvinylpyrrolidone etc., lubricant is like Pulvis Talci, magnesium stearate etc.
The Progesterone supersaturated self-emulsion composition of the present invention's preparation is solubilized into Progesterone in oil-in-water type (O/W) microemulsion of 10-90nm on the one hand; Improved dissolubility and the dissolution rate of Progesterone in gastro-intestinal Fluid, solved that Progesterone is low owing to dissolubility, the low problem of the limited oral administration biaavailability that causes of stripping; On the other hand; In the microemulsion that forms behind the Progesterone supersaturation self-microemulsion oral is encapsulated in Progesterone in non-natural plant oil and the surfactant layer, thereby the protection Progesterone avoids the degraded of acid and enzyme in the gastrointestinal tract, and stabilizing agent suppresses the Progesterone crystallization and separates out in the microemulsion dilution; Increase the Progesterone saturation solubility; Form the Progesterone supersaturated solution, can further increase the absorption of Progesterone, thereby Progesterone supersaturation microemulsion can have been avoided liver first-pass effect through the lymph absorption simultaneously; As a kind of original new drug novel form, the present invention possesses characteristics such as low viscosity, steady quality, and improves drug absorption, improves bioavailability, reduces toxicity; Compared with prior art; The present invention has the following advantages:
do not have moisture in the Progesterone supersaturated self-emulsion system; Therefore more stable than progesterone injection; Can also be developed into various peroral dosage forms; Easy to carry, patient's compliance is good; And the corpus luteum injection can only drug administration by injection and untoward reaction more, patient's compliance is poor; The microemulsion particle size distribution is 0.1-1.5 μ m in the particle diameter of 10-90nm Progesterone sub-microemulsion injection behind
Progesterone supersaturated self-emulsion self-emulsifying microemulsion; Particle diameter is more little; The medicine dispersion is high more; It is good more to absorb, and particle diameter is more little simultaneously, and system is stable more; In addition, the said most emulsive methods of two steps that adopt of prior art need the acting of high pressure homogenizer external force; Technology is loaded down with trivial details; By comparison, the preparation of Progesterone supersaturated self-emulsion composition of the present invention does not need special installation, and preparation technology is simple; Effectively reduce the required time of preparation process, greatly reduced energy consumption.
If not refer in particular to, all chemical reagent, raw material such as the used non-natural plant oil of the present invention, emulsifying agent, stabilizing agent are the commercial goods.
Progesterone supersaturated self-emulsion composition of the present invention is following to assimilation effect pharmacokinetic in the animal body:
Get Progesterone 8.0%, MCT Oil 18.5%, glyceryl linoleate 18.5%; Polyoxyethylene castor oil 30.0%, sad capric acid polyethyleneglycol glyceride 6.0%, TC 18.0%; Hypromellose 1.0%; Prepare the Progesterone supersaturated self-emulsion composition with the inventive method, with commercially available Progesterone soft gelatin capsule (specification: the 100mg/ grain, manufacturer: be reference preparation Aisheng Pharmaceutical Co., Ltd., Zhejiang):
Get 6 of male Beagle dogs, be divided into two groups of A, B at random, 3 every group; Fasting can't help water 12 hours before the experiment, and A group single dose 8mg/kg irritates stomach and gives Progesterone supersaturated self-emulsion preparation of the present invention, and B group single dose is irritated stomach and given 8mg/kg Progesterone soft gelatin capsule; The different time points left fore is got blood 1mL and is put in the calparine pipe before administration, after the administration; The centrifugal 10min of 3500rpm/min, separated plasma is preserved for use in subzero 80 ℃ of refrigerators; The Beagle dog breeders is after 1 week, and A group single dose 8mg/kg irritates stomach and gives the Progesterone soft gelatin capsule, and B group single dose 8mg/kg irritates stomach and gives the Progesterone supersaturated self-emulsion, after the administration by different time points last time get preserve in blood, separated plasma, the subzero 80 ℃ of refrigerators for use;
Plasma sample is analyzed: precision pipettes blood plasma 0.2mL, accurate 1.0mL ethyl acetate, the whirlpool mixing 3min of adding; 5000rpm/min high speed centrifugation 10min; Get 40 ℃ of nitrogen of supernatant and dry up, add 100 μ L60% dissolve with methanol residues, whirlpool mixing 2min; 10000rpm/min high speed centrifugation 10min gets supernatant with progesterone concentrations in the high-performance liquid chromatogram determination blood plasma;
Calculating relative bioavailability by AUC is 645.4%, sees Fig. 2, and the result shows that the Progesterone supersaturated self-emulsion composition has significantly improved the Progesterone oral administration biaavailability with respect to the Progesterone soft gelatin capsule.
Description of drawings
Fig. 1 is the particle size distribution figure of Progesterone supersaturated self-emulsion composition after the water dilution of the embodiment of the invention 8 preparations.
Fig. 2 for Progesterone supersaturated self-emulsion composition of the present invention and Progesterone soft gelatin capsule at Beagle dog vivo medicine concentration-time plot.
The specific embodiment
Below in conjunction with accompanying drawing embodiments of the invention are elaborated: present embodiment provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment being to implement under the prerequisite with technical scheme of the present invention.
A kind of prescription component and percentage by weight thereof of Progesterone supersaturated self-emulsion composition:
Progesterone 0.5%, MCT Oil 30.0%, polyoxyethylene castor oil 30.0%, sad capric acid polyethyleneglycol glyceride 16.0%, PEG400 23.0%, hypromellose 0.5%.
Progesterone supersaturated self-emulsion composition preparation technology is in the present embodiment: the MCT Oil and the PEG400 of recipe quantity are mixed, stir; With the Progesterone of recipe quantity at 30 ℃ of-40 ℃ of following ultrasonic dissolutions in the mixed liquor of MCT Oil and PEG400; After the cooling; Add recipe quantity polyoxyethylene castor oil and sad capric acid polyethyleneglycol glyceride; Magnetic agitation is even, adds dissolving of recipe quantity hypromellose or suspendible then wherein, promptly gets the Progesterone supersaturated self-emulsion composition.
After 100 times of the water dilutions, adopting Ma Erwen granularity potential measurement appearance (Nano-ZS90) to measure particle size distribution is 39.1nm.
The beneficial effect of present embodiment is: the Progesterone supersaturated self-emulsion composition of (1) the present invention preparation forms in the o/w microemulsion of 39.1 nm after absorbing gastrointestinal tract moisture; Because particle diameter is little; The medicine degree of scatter is high, thereby has increased the degree of absorption of medicine, improves its bioavailability; (2) Progesterone dissolves compound for shipwreck property, document [Wang Xianying, the development of revolving the firm Progesterone Benexate Hydrochloride of will; The Chinese Hospitals pharmaceutical journal, 2003,23 (12): 719-721] report that Progesterone dissolubility in water is about 9.33 * 10
-3Mg/mL, the Progesterone supersaturated self-emulsion composition is solubilized into Progesterone in the o/w microemulsion of 10-90nm in the present embodiment, and the content of Progesterone is 5mg/g, has improved dissolubility and the dissolution rate of Progesterone in gastro-intestinal Fluid; (3) microemulsion that forms behind the Progesterone supersaturation self-microemulsion oral is encapsulated in Progesterone in interior non-natural plant oil and the surfactant layer; Thereby the protection Progesterone avoids in the gastrointestinal tract degraded of acid and enzyme; Thereby the Progesterone microemulsion can absorb through lymph and avoid liver first-pass effect simultaneously, has improved the Progesterone oral administration biaavailability; (4) crystallization of hypromellose inhibition dilution Chinese medicine is separated out, and has increased the Progesterone saturation solubility, forms the Progesterone supersaturated solution, has increased drug absorption.
A kind of prescription component and percentage by weight thereof of Progesterone supersaturated self-emulsion composition:
Progesterone 2.0%, ethyl oleate 40%, polyoxyethylene hydrogenated Oleum Ricini 30.0%, polyoxyethylene sorbitan monoleate 12.0%, PEG400 15.0%, polyvinylpyrrolidone 1%.
Progesterone supersaturated self-emulsion composition preparation technology is in the present embodiment: the ethyl oleate and the PEG400 of recipe quantity are mixed, stir; With the Progesterone of recipe quantity at 30 ℃ of-40 ℃ of following ultrasonic dissolutions in the mixed liquor of ethyl oleate and PEG400; After the cooling; Add recipe quantity polyoxyethylene hydrogenated Oleum Ricini and polyoxyethylene sorbitan monoleate; Magnetic agitation is even, adds dissolving of recipe quantity polyvinylpyrrolidone or suspendible then wherein, promptly gets the Progesterone supersaturated self-emulsion composition.
Method for preparing is with embodiment 1.After 100 times of the water dilutions, adopting Ma Erwen granularity potential measurement appearance (Nano-ZS90) to measure particle size distribution is 58.62nm.
The beneficial effect of present embodiment is: the Progesterone supersaturated self-emulsion composition of (1) the present invention preparation forms in the o/w microemulsion of 58.62 nm after absorbing gastrointestinal tract moisture; Because particle diameter is little; The medicine degree of scatter is high, thereby has increased the degree of absorption of medicine, improves its bioavailability; (2) the Progesterone supersaturated self-emulsion composition is solubilized into Progesterone in the o/w microemulsion of 10-90nm in the present embodiment, and the content of Progesterone is 20mg/g, has improved dissolubility and the dissolution rate of Progesterone in gastro-intestinal Fluid; (3) microemulsion that forms behind the Progesterone supersaturation self-microemulsion oral is encapsulated in Progesterone in interior non-natural plant oil and the surfactant layer; Thereby the protection Progesterone avoids in the gastrointestinal tract degraded of acid and enzyme; Thereby the Progesterone microemulsion can absorb through lymph and avoid liver first-pass effect simultaneously, has improved the Progesterone oral administration biaavailability; (4) crystallization of polyvinylpyrrolidone inhibition dilution Chinese medicine is separated out, and has increased the Progesterone saturation solubility, forms the Progesterone supersaturated solution, has increased drug absorption.
A kind of prescription component and percentage by weight thereof of Progesterone supersaturated self-emulsion composition:
Progesterone 4.3%, ethyl oleate 29.7%, polyoxyethylene castor oil 40.0%, sad capric acid polyethyleneglycol glyceride 6.0%, TC 15.0%, polyvinylpyrrolidone 5%.
Method for preparing is with embodiment 1.After 100 times of the water dilutions, adopting Ma Erwen granularity potential measurement appearance (Nano-ZS90) to measure particle size distribution is 31.97 nm.
The beneficial effect of present embodiment is: the Progesterone supersaturated self-emulsion composition of (1) the present invention preparation forms in the o/w microemulsion of 31.97 nm after absorbing gastrointestinal tract moisture; Because particle diameter is little; The medicine degree of scatter is high, thereby has increased the degree of absorption of medicine, improves its bioavailability; (2) the Progesterone supersaturated self-emulsion composition is solubilized into Progesterone in the o/w microemulsion of 10-90nm in the present embodiment, and the content of Progesterone is 43mg/g, has improved dissolubility and the dissolution rate of Progesterone in gastro-intestinal Fluid; (3) microemulsion that forms behind the Progesterone supersaturation self-microemulsion oral is encapsulated in Progesterone in interior non-natural plant oil and the surfactant layer; Thereby the protection Progesterone avoids in the gastrointestinal tract degraded of acid and enzyme; Thereby the Progesterone microemulsion can absorb through lymph and avoid liver first-pass effect simultaneously, has improved the Progesterone oral administration biaavailability; (4) crystallization of polyvinylpyrrolidone inhibition dilution Chinese medicine is separated out, and has increased the Progesterone saturation solubility, forms the Progesterone supersaturated solution, has increased drug absorption.
Embodiment 4
A kind of prescription component and percentage by weight thereof of Progesterone supersaturated self-emulsion composition:
Progesterone 4.6%, ethyl oleate 38.4%, polyoxyethylene hydrogenated Oleum Ricini 32.0%, PEG400 15.0%, sad capric acid polyethyleneglycol glyceride 8.0%, polyvinylpyrrolidone 2.0%.
Method for preparing is with embodiment 1.After 100 times of the water dilutions, adopting Ma Erwen granularity potential measurement appearance (Nano-ZS90) to measure particle size distribution is 44.21 nm.
The beneficial effect of present embodiment is: the Progesterone supersaturated self-emulsion composition of (1) the present invention preparation forms in the o/w microemulsion of 44.21 nm after absorbing gastrointestinal tract moisture; Because particle diameter is little; The medicine degree of scatter is high, thereby has increased the degree of absorption of medicine, improves its bioavailability; (2) the Progesterone supersaturated self-emulsion composition is solubilized into Progesterone in the o/w microemulsion of 10-90nm in the present embodiment, and the content of Progesterone is 46mg/g, has improved dissolubility and the dissolution rate of Progesterone in gastro-intestinal Fluid; (3) microemulsion that forms behind the Progesterone supersaturation self-microemulsion oral is encapsulated in Progesterone in interior non-natural plant oil and the surfactant layer; Thereby the protection Progesterone avoids in the gastrointestinal tract degraded of acid and enzyme; Thereby the Progesterone microemulsion can absorb through lymph and avoid liver first-pass effect simultaneously, has improved the Progesterone oral administration biaavailability; (4) crystallization of polyvinylpyrrolidone inhibition dilution Chinese medicine is separated out, and has increased the Progesterone saturation solubility, forms the Progesterone supersaturated solution, has increased drug absorption.
A kind of prescription component and percentage by weight thereof of Progesterone supersaturated self-emulsion composition:
Progesterone 5.6%, glyceryl linoleate 23.6%, polyoxyethylene castor oil 39.8%, sad capric acid polyethyleneglycol glyceride 13.0%, TC 17.0%, hypromellose 1.0%.
Method for preparing is with embodiment 1.After 100 times of the water dilutions, adopting Ma Erwen granularity potential measurement appearance (Nano-ZS90) to measure particle size distribution is 26.37 nm.
The beneficial effect of present embodiment is: the Progesterone supersaturated self-emulsion composition of (1) the present invention preparation forms in the o/w microemulsion of 26.37 nm after absorbing gastrointestinal tract moisture; Because particle diameter is little; The medicine degree of scatter is high, thereby has increased the degree of absorption of medicine, improves its bioavailability; (2) the Progesterone supersaturated self-emulsion composition is solubilized into Progesterone in the o/w microemulsion of 10-90nm in the present embodiment, and the content of Progesterone is 56mg/g, has improved dissolubility and the dissolution rate of Progesterone in gastro-intestinal Fluid; (3) microemulsion that forms behind the Progesterone supersaturation self-microemulsion oral is encapsulated in Progesterone in interior non-natural plant oil and the surfactant layer; Thereby the protection Progesterone avoids in the gastrointestinal tract degraded of acid and enzyme; Thereby the Progesterone microemulsion can absorb through lymph and avoid liver first-pass effect simultaneously, has improved the Progesterone oral administration biaavailability; (4) crystallization of hypromellose inhibition dilution Chinese medicine is separated out, and has increased the Progesterone saturation solubility, forms the Progesterone supersaturated solution, has increased drug absorption.
Embodiment 6
A kind of prescription component and percentage by weight thereof of Progesterone supersaturated self-emulsion composition:
Progesterone 2.0%, Ethyl linoleate 40.0%, polyoxyethylene hydrogenated Oleum Ricini 20.0%, sad capric acid polyethyleneglycol glyceride 17.5%, PEG400 18.5%, polyethylene glycol 6000 2.0%.
Method for preparing is with embodiment 1.After 100 times of the water dilutions, adopting Ma Erwen granularity potential measurement appearance (Nano-ZS90) to measure particle size distribution is 52.00 nm.
The beneficial effect of present embodiment is: the Progesterone supersaturated self-emulsion composition of (1) the present invention preparation forms in the o/w microemulsion of 52.00 nm after absorbing gastrointestinal tract moisture; Because particle diameter is little; The medicine degree of scatter is high, thereby has increased the degree of absorption of medicine, improves its bioavailability; (2) the Progesterone supersaturated self-emulsion composition is solubilized into Progesterone in the o/w microemulsion of 10-90nm in the present embodiment, and the content of Progesterone is 20mg/g, has improved dissolubility and the dissolution rate of Progesterone in gastro-intestinal Fluid; (3) microemulsion that forms behind the Progesterone supersaturation self-microemulsion oral is encapsulated in Progesterone in interior non-natural plant oil and the surfactant layer; Thereby the protection Progesterone avoids in the gastrointestinal tract degraded of acid and enzyme; Thereby the Progesterone microemulsion can absorb through lymph and avoid liver first-pass effect simultaneously, has improved the Progesterone oral administration biaavailability; (4) crystallization of polyethylene glycol 6000 inhibition dilution Chinese medicine is separated out, and has increased the Progesterone saturation solubility, forms the Progesterone supersaturated solution, has increased drug absorption.
Embodiment 7
A kind of prescription component and percentage by weight thereof of Progesterone supersaturated self-emulsion composition:
Progesterone 4.3 %, Ethyl linoleate 38.0%, polyoxyethylene castor oil 19.2%, polyoxyethylene sorbitan monoleate 18.5%, PEG400 18.5%, polyvinylpyrrolidone 1.5%.
Method for preparing is with embodiment 1.After 100 times of the water dilutions, adopting Ma Erwen granularity potential measurement appearance (Nano-ZS90) to measure particle size distribution is 50.57 nm.
The beneficial effect of present embodiment is: the Progesterone supersaturated self-emulsion composition of (1) the present invention preparation forms in the o/w microemulsion of 50.57 nm after absorbing gastrointestinal tract moisture; Because particle diameter is little; The medicine degree of scatter is high, thereby has increased the degree of absorption of medicine, improves its bioavailability; (2) the Progesterone supersaturated self-emulsion composition is solubilized into Progesterone in the o/w microemulsion of 10-90nm in the present embodiment, and the content of Progesterone is 43mg/g, has improved dissolubility and the dissolution rate of Progesterone in gastro-intestinal Fluid; (3) microemulsion that forms behind the Progesterone supersaturation self-microemulsion oral is encapsulated in Progesterone in interior non-natural plant oil and the surfactant layer; Thereby the protection Progesterone avoids in the gastrointestinal tract degraded of acid and enzyme; Thereby the Progesterone microemulsion can absorb through lymph and avoid liver first-pass effect simultaneously, has improved the Progesterone oral administration biaavailability; (4) crystallization of polyvinylpyrrolidone inhibition dilution Chinese medicine is separated out, and has increased the Progesterone saturation solubility, forms the Progesterone supersaturated solution, has increased drug absorption.
Embodiment 8
A kind of prescription component and percentage by weight thereof of Progesterone supersaturated self-emulsion composition:
Progesterone 6.5%, MCT Oil 18.0%, glyceryl linoleate 18.0%, polyoxyethylene hydrogenated Oleum Ricini 35.0%, sad capric acid polyethyleneglycol glyceride 7.0%, TC 14.0%, hypromellose 1.5%.
Method for preparing is with embodiment 1.After 100 times of the water dilutions, adopting Ma Erwen granularity potential measurement appearance (Nano-ZS90) to measure particle size distribution is 31.42nm.The particle diameter of dilution back microemulsion is 0,1, and particle diameter is respectively 31.70,32.43,32.48,32.45,32.91 in the time of 2,4,8 hours, and no significance changes.
The beneficial effect of present embodiment is: the Progesterone supersaturated self-emulsion composition of (1) the present invention preparation forms in the o/w microemulsion of 31.42 nm after absorbing gastrointestinal tract moisture; Because particle diameter is little; The medicine degree of scatter is high, thereby has increased the degree of absorption of medicine, improves its bioavailability; (2) the Progesterone supersaturated self-emulsion composition is solubilized into Progesterone in the o/w microemulsion of 10-90nm in the present embodiment, and the content of Progesterone is 65mg/g, has improved dissolubility and the dissolution rate of Progesterone in gastro-intestinal Fluid; (3) microemulsion that forms behind the Progesterone supersaturation self-microemulsion oral is encapsulated in Progesterone in interior non-natural plant oil and the surfactant layer; Thereby the protection Progesterone avoids in the gastrointestinal tract degraded of acid and enzyme; Thereby the Progesterone microemulsion can absorb through lymph and avoid liver first-pass effect simultaneously, has improved the Progesterone oral administration biaavailability; (4) crystallization of hypromellose inhibition dilution Chinese medicine is separated out, and has increased the Progesterone saturation solubility, forms the Progesterone supersaturated solution, has increased drug absorption.
Embodiment 9
A kind of prescription component and percentage by weight thereof of Progesterone supersaturated self-emulsion composition:
Progesterone 5.3%, MCT Oil 14.0 %, glyceryl linoleate 14.0 %, polyoxyethylene hydrogenated Oleum Ricini 30.0%, polyoxyethylene sorbitan monoleate 15.0%, isopropyl alcohol 21.0%, hypromellose 0.7%.
Method for preparing is with embodiment 1.After 100 times of the water dilutions, adopting Ma Erwen granularity potential measurement appearance (Nano-ZS90) to measure particle size distribution is 26.81nm.
The beneficial effect of present embodiment is: the Progesterone supersaturated self-emulsion composition of (1) the present invention preparation forms in the o/w microemulsion of 26.81 nm after absorbing gastrointestinal tract moisture; Because particle diameter is little; The medicine degree of scatter is high, thereby has increased the degree of absorption of medicine, improves its bioavailability; (2) the Progesterone supersaturated self-emulsion composition is solubilized into Progesterone in the o/w microemulsion of 10-90nm in the present embodiment, and the content of Progesterone is 53mg/g, has improved dissolubility and the dissolution rate of Progesterone in gastro-intestinal Fluid; (3) microemulsion that forms behind the Progesterone supersaturation self-microemulsion oral is encapsulated in Progesterone in interior non-natural plant oil and the surfactant layer; Thereby the protection Progesterone avoids in the gastrointestinal tract degraded of acid and enzyme; Thereby the Progesterone microemulsion can absorb through lymph and avoid liver first-pass effect simultaneously, has improved the Progesterone oral administration biaavailability; (4) crystallization of hypromellose inhibition dilution Chinese medicine is separated out, and has increased the Progesterone saturation solubility, forms the Progesterone supersaturated solution, has increased drug absorption.
A kind of prescription component and percentage by weight thereof of Progesterone supersaturated self-emulsion composition:
Progesterone 8.0%, MCT Oil 18.5%, glyceryl linoleate 18.5%, polyoxyethylene castor oil 30.0%, sad capric acid polyethyleneglycol glyceride 6.0%, TC 18.0%, hypromellose 1.0%.
Method for preparing is with embodiment 1.After 100 times of the water dilutions, adopting Ma Erwen granularity potential measurement appearance (Nano-ZS90) to measure particle size distribution is 34.28nm.
The beneficial effect of present embodiment is: the Progesterone supersaturated self-emulsion composition of (1) the present invention preparation forms in the o/w microemulsion of 34.28 nm after absorbing gastrointestinal tract moisture; Because particle diameter is little; The medicine degree of scatter is high, thereby has increased the degree of absorption of medicine, improves its bioavailability; (2) the Progesterone supersaturated self-emulsion composition is solubilized into Progesterone in the o/w microemulsion of 10-90nm in the present embodiment, and the content of Progesterone is 80mg/g, has improved dissolubility and the dissolution rate of Progesterone in gastro-intestinal Fluid; (3) microemulsion that forms behind the Progesterone supersaturation self-microemulsion oral is encapsulated in Progesterone in interior non-natural plant oil and the surfactant layer; Thereby the protection Progesterone avoids in the gastrointestinal tract degraded of acid and enzyme; Thereby the Progesterone microemulsion can absorb through lymph and avoid liver first-pass effect simultaneously, has improved the Progesterone oral administration biaavailability; (4) crystallization of hypromellose inhibition dilution Chinese medicine is separated out, and has increased the Progesterone saturation solubility, forms the Progesterone supersaturated solution, has increased drug absorption.
Claims (10)
1. Progesterone supersaturated self-emulsion composition, form by weight percentage by following composition:
Progesterone 0.5%-8%
Non-natural plant oil 10%-55%
Polyoxyethylene castor oil or polyoxyethylene hydrogenated Oleum Ricini 15%-40%
Polyoxyethylene sorbitan monoleate or sad capric acid polyethyleneglycol glyceride 5%-20%
Co-emulsifier 5%-30%
Stabilizing agent 0.1-5%.
2. Progesterone supersaturated self-emulsion composition as claimed in claim 1; It is characterized in that described non-natural plant oil is ethyl oleate; MCT Oil; Glyceryl linoleate, Ethyl linoleate, MCT Oil and glyceryl linoleate or oleic one or more mixture.
3. Progesterone supersaturated self-emulsion as claimed in claim 1 is characterized in that described co-emulsifier is PEG400, TC, isopropyl alcohol, ethanol, 1, wherein one or more the mixture of 2-propylene glycol.
4. Progesterone supersaturated self-emulsion composition as claimed in claim 1 is characterized in that described stabilizing agent is one or several in polyvinylpyrrolidone, hypromellose, dextran, arabic gum, gelatin, the Polyethylene Glycol of molecular weight more than 1000.
5. Progesterone supersaturated self-emulsion composition as claimed in claim 1, form by weight percentage by following composition:
Progesterone 8.0%
MCT Oil 18.5%
Glyceryl linoleate 18.5%
Polyoxyethylene castor oil 30.0%
Sad capric acid polyethyleneglycol glyceride 6.0%
TC 18.0%
Hypromellose 1.0%.
6. like claim 1 or 5 described Progesterone supersaturated self-emulsion compositions, it is characterized in that the ratio of described polyoxyethylene castor oil or polyoxyethylene hydrogenated Oleum Ricini and sad capric acid polyethyleneglycol glyceride or polyoxyethylene sorbitan monoleate is 1:1～5:1.
7. like claim 1 or 5 described Progesterone supersaturated self-emulsion compositions, it is characterized in that the mass ratio of described polyoxyethylene castor oil or polyoxyethylene hydrogenated Oleum Ricini, polyoxyethylene sorbitan monoleate or sad capric acid polyethyleneglycol glyceride and co-emulsifier is 1:1-4:1.
8. like the method for preparing of claim 1 or 5 described Progesterone supersaturated self-emulsion compositions, comprise the steps:
(1) under the room temperature, non-natural plant oil and co-emulsifier mixing with recipe quantity stir;
(2) Progesterone with recipe quantity carries out ultrasonic Treatment, and Progesterone is dissolved in the mixed liquor of non-natural plant oil and co-emulsifier of step (1);
(3) mixed liquor with step (2) is cooled to room temperature; The polyoxyethylene castor oil or polyoxyethylene hydrogenated Oleum Ricini and sad capric acid polyethyleneglycol glyceride or the polyoxyethylene sorbitan monoleate that add recipe quantity; The use magnetic stirrer is even, adds stabilizing agent dissolving or suspendible then and wherein promptly gets the Progesterone supersaturated self-emulsion composition;
(4) give medically acceptable carrier with the Progesterone self-emulsion composition, be prepared into tablet, capsule, soft capsule, oral liquid, oral gel or granule.
9. the method for preparing of Progesterone supersaturated self-emulsion composition as claimed in claim 8, the temperature when it is characterized in that carrying out ultrasonic Treatment are that 30 ℃-40 ℃, power are that 40w, supersound process time are 30min.
10. the method for preparing of Progesterone supersaturated self-emulsion composition as claimed in claim 8; When it is characterized in that described Progesterone supersaturated self-emulsion composition is diluted to microemulsion with the water of arbitrary proportion; Its particle size distribution is between 10-90nm, and the microemulsion that obtains after dilution particle diameter in 8 hours does not have significance to be changed.
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| CN110623926A (en) * | 2019-10-31 | 2019-12-31 | 沈阳药科大学 | Panaxatriol supersaturated self-microemulsion and preparation method thereof |
| WO2020103952A1 (en) * | 2018-11-22 | 2020-05-28 | 南京诺瑞特医药科技有限公司 | New neuroactive steroid preparation |
| CN111529488A (en) * | 2020-06-16 | 2020-08-14 | 杭州同惠医药科技有限公司 | Progesterone self-emulsifying composition and application thereof |
| CN116077416A (en) * | 2021-11-05 | 2023-05-09 | 深圳埃格林医药有限公司 | Novel oral preparation containing progestogen and preparation method and application thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105963687A (en) * | 2016-04-27 | 2016-09-28 | 张金凤 | Compound preparation for treating chronic pelvic pain and preparation method of compound preparation |
| WO2020103952A1 (en) * | 2018-11-22 | 2020-05-28 | 南京诺瑞特医药科技有限公司 | New neuroactive steroid preparation |
| CN111281877A (en) * | 2018-11-22 | 2020-06-16 | 南京诺瑞特医药科技有限公司 | New formulations of neuroactive steroids |
| CN110623926A (en) * | 2019-10-31 | 2019-12-31 | 沈阳药科大学 | Panaxatriol supersaturated self-microemulsion and preparation method thereof |
| CN110623926B (en) * | 2019-10-31 | 2022-05-20 | 沈阳药科大学 | Panaxatriol supersaturated self-microemulsion and preparation method thereof |
| CN111529488A (en) * | 2020-06-16 | 2020-08-14 | 杭州同惠医药科技有限公司 | Progesterone self-emulsifying composition and application thereof |
| CN116077416A (en) * | 2021-11-05 | 2023-05-09 | 深圳埃格林医药有限公司 | Novel oral preparation containing progestogen and preparation method and application thereof |
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|---|---|
| CN102415995B (en) | 2013-11-13 |
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