CN102652733A - Natural progesterone proliposome preparation and preparation method and using method thereof - Google Patents
Natural progesterone proliposome preparation and preparation method and using method thereof Download PDFInfo
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Abstract
The invention discloses a natural progesterone proliposome preparation and a preparation method and a using method thereof. The natural progesterone proliposome preparation contains 1 to 30 percent of progesterone in percentage by weight, and is prepared from progesterone, phosphatide, 1,2-propanediol or/and poly(ethylene glycol)-400 (PEG-400). The natural progesterone proliposome preparation is diluted with water before being taken, or is orally taken into a body, and contacts body fluid, and the phosphatide is hydrated and self-assembled to form liposome. The natural progesterone proliposome preparation avoids metabolizing of progesterone in gastrointestinal tracts and reduces the first pass effect by using a wrapping function of the liposome, and cellular barriers can be changed by using the liposome so as to promote transmembrane transport and inhibit P-glycoprotein to realize slow releasing; and the natural progesterone proliposome preparation has the functions of good cytocompatibility, promotion of lymphatic transport and the like so as to promote gastrointestinal absorption of natural progesterone. Meanwhile, the natural progesterone proliposome preparation can be further modified by chitosan which promotes absorption and has strong adhesivity to further improve the bioavailability of the progesterone. Therefore, the natural progesterone proliposome preparation is a novel preparation which improves the absorption and the bioavailability of the progesterone after oral administration from a variety of mechanism and a plurality of angles.
Description
Technical field
the present invention relates to medical technical field, are a kind of natural progesterone proliposome preparation and preparation method thereof and method for using.
Background technology
Progesterone (Progesterone) has another name called progesterone, gestogen, pregnendione, is a kind of natural progestogen that exists in the body.Natural progesterone is used in clinical very extensively, is used to treat secondary amenorrhea, dysfunctional uterine hemorrhage, support luteal phase, premature labor, inadequate luteal function, premenstrual syndrome, habitual abortion, threatened abortion etc.And Progesterone is at external fertilization---play an important role in the transplantation of embryo (IVF), be keep gestation requisite.Along with people's growth in the living standard in addition; Increasing women after menopause complementing estrogen to improve the quality of living, promptly the hormonal supplementation therapy (Hormone replacement therapy, HRT); In the hormonal supplementation therapy; Take the progestogens medicine simultaneously and can prevent to take for a long time the caused endometrial hyperplasia of estrogen, reduce because of single and suffer from the risk of carcinoma of endometrium with the caused postmenopausal women of estrogen, and prevention of osteoporosis and periodontal better.In the hormonal supplementation therapy, use synthetic progestin class medicine and be prone to produce patient's high density lipoprotein (HDL) and change, disturb carbohydrate metabolism, and side effect such as headache, mood change, fetus are manlike, teratogenesis.Progesterone is the natural progestogen that exists in a kind of body, is difficult for producing synthetic progestin class side effects of pharmaceutical drugs, and therefore, the natural progesterone preparation has great clinical demand in the HRT therapy.Along with the broader applications of IVF and HRT, the clinical value of Progesterone can be increasing.
but the Progesterone water solublity is low, oral back is prone to by enzymatic degradation in the gastrointestinal tract, the first pass effect that tool is strong, the half-life is extremely lacked (being merely 5 minutes), and bioavailability is very low, generally uses as intramuscular injection clinically.Because of Progesterone needs long term administration; Intramuscular administration has brought great inconvenience to the patient, and the Progesterone injection is oil solution, injection back pain; Long term administration also can make medicine-feeding part produce atrophy; Therefore, increase and need under the prerequisite of long-term prescription in the clinical practice demand of Progesterone, exploitation Progesterone new formulation seems particularly important.
The problem of Progesterone novel formulation is developed at present to the bioavailability that improves Progesterone in
, the domestic research that also has many researcheres to carry out this respect, but still there is certain limitation in these researchs.Like the refined patent No. of force is that the Chinese patent document of ZL200410040615.3 discloses Progesterone membrane and preparation method thereof.It is to use the Progesterone of effective dose to be active component; Add that film property material, surfactant and other adjuvant or complementary composition are prepared into membrane; Adopt vagina administration in the hope of reducing serum progesterone concentrations, reduce side effect, and produce higher endometrium progesterone concentrations.But the related membrane of this invention exists drug loading little, and the shortcoming that administration is inconvenient is because of Progesterone needs long term administration, so membrane can not be desirable first-selected as progesterone preparation.
The patent No. of
Gu Linjin and Wang Guowei is that the Chinese patent document of ZL 03116174.X discloses a kind of oral Progesterone semi-solid skeleton preparation and compositions.Its component and content comprise: Progesterone quality percentage composition is 0.5% to 10%, HLB> Surfactant quality percentage composition more than 12 is 1% to 98.5%.This invention is through the compositions of preparation Progesterone semi-solid skeleton preparation; Utilize the short Absorption of surfactant itself simultaneously; Expectation can significantly increase progestogen concentration in the blood, improves various symptoms and disease due to progestogen for want of or the Progesterone insufficiency of function.But comprise a large amount of surfactants in this invention prescription, certain infringements that a large amount of oral backs of surfactant exist gastrointestinal mucosa, and this invention to fail fundamentally to solve the Progesterone internal metabolism fast, the problem that bioavailability is low.
The patent No. of
Shen Zhiqun is that the Chinese patent document of ZL02136639.X discloses oral Progesterone Capsule Composite and Preparation Method, and its prescription mainly comprises Progesterone, carrier, organic solvent, surfactant, micropowder silica gel, starch etc.Method for preparing mainly is in the carrier adding organic solvent of elder generation with recipe quantity, is heated to 60 ℃, adds Progesterone again and makes its dissolving; 40 ℃ of vacuum dryings 4 hours, comminution by gas stream adds micropowder silica gel, starch uniform mixing; Capsulation gets final product; But this invention only reaches the purpose that improves the Progesterone bioavailability through absorbing in the body that promotes Progesterone, can not solve the problem of Progesterone internal metabolism, and big (400mg/ day) just can reach curative effect so dosage still needs very; Dosage is big more, and the toxic and side effects of medicine will certainly be big more.So this invention can not be as the optimal choice of Progesterone oral formulations.
The Chinese patent document of the ZL02157710.2 of
Gu Linjin, Wang Guowei discloses a kind of oral capsule pill that contains Progesterone; Include the transparent liquid thing that Progesterone and solubilizing agent, surfactant adjuvants such as (for Tween-20, Tween-80) is processed, process as outer covering material with gelatin.When this invention mainly is utilized in the digestive tract absorption; The principle that the absorbance of medicine and dissolution velocity are directly proportional; Adopt the good polyhydric alcohol dissolving Progesterone of high surfactant of HLB and solubility property,, improve its dissolution velocity to increase the hydrophilic of Progesterone; And then the absorbance of raising Progesterone; But Progesterone and surfactant are simple course of dissolution in solvent in this invention, and the Progesterone hydrophilic increases limited, and a large amount of poly yamanashi esters surfactant is present in the toxicity that also can increase preparation in the preparation.
The patent No. of
Fan Minhua is that the Chinese patent document of ZL200410004704.2 discloses a kind of Progesterone liquid capsule and preparation method thereof, and content is made up of in Progesterone and excipient substance such as vegetable oil, Cera Flava, lecithin, gelatin, glycerol, tween 80, the span one or more.In proportion with Progesterone and pharmaceutic adjuvant under 20 to 100 ℃, the even mode of stirring or mechanical agitation or high pressure breast by hand, dissolving or mixing are filled in mixture in the capsule shells then, promptly get with adhesive seal.Progesterone liquid capsule content is liquid or semisolid in this invention, so can reach rapid onset in vivo, improves the purpose of bioavailability.But this invention just utilizes liquid or semi-solid faster than solid dissolution velocity; A certain amount of surfactant can promote the principle of drug absorption to improve drug bioavailability; So it is limited that this method improves the degree of Progesterone bioavailability; It is strong fundamentally to solve the Progesterone first pass effect, the problem that bioavailability is low.
also have the patent report of Progesterone Sublingual effervescent tablet and Progesterone percutaneous preparation in addition, the limitation of dosage form itself but these are invented, and degree of absorption is all limited, so can not be as the first-selection of progesterone preparation.
Summary of the invention
the invention provides a kind of natural progesterone proliposome preparation and preparation method thereof and method for using; Overcome the deficiency of above-mentioned prior art, it can effectively solve the problem that the Progesterone bioavailability is low, the toxic and side effects of medicine is big and administration is inconvenient.
One of
technical scheme of the present invention realizes through following measure: a kind of natural progesterone proliposome preparation: percent contains Progesterone 1% to 30% by weight; Phosphatidase 11 0% to 30%; 1 of surplus, the 2-propylene glycol is or/and PEG-400.
Be to the further optimization of one of foregoing invention technical scheme below or/and improve:
are above-mentioned 1, and the volume ratio of 2-propylene glycol and PEG-400 is 2: 1-3: 1.
The concentration of
above-mentioned Progesterone is 50 milligrams every milliliter, so this dosage form has bigger drug loading.
above-mentioned phospholipid is oral soybean phospholipid or injection phospholipid or other synthetic phospholipid.
Two of
technical scheme of the present invention realizes through following measure: a kind of production method of natural progesterone proliposome preparation: undertaken by following step: at first Progesterone and phospholipid are joined 1; The 2-propylene glycol is or/and in the solvent of PEG-400; Under anhydrous condition, mix; The temperature of heating and maintenance mixture makes mixture be dissolved into clear and bright anhydrous solution at 50 ℃ to 70 ℃; Perhaps clear and bright anhydrous solution is further wrapped up with chitosan material; Perhaps clear and bright anhydrous solution is wrapped in the soft capsule; Obtain the natural progesterone proliposome preparation.
Three of
technical scheme of the present invention realizes through following measure: a kind of method for using of natural progesterone proliposome preparation: thin up or direct oral back got in the body before this natural progesterone proliposome preparation was taken; Contact with water or body fluid, phospholipid hydration self assembly forms liposome.
the present invention is through Progesterone, phospholipid, 1, and the 2-propylene glycol is or/and PEG-400 processes the natural progesterone proliposome preparation, and thin up or oral back get in the body before taking; Contact body fluid; Phospholipid hydration self assembly forms liposome, and this preparation has bigger drug loading, and this preparation is to utilize the package action of liposome to avoid Progesterone metabolism in vivo; Reduce first pass effect; Utilize liposome to change barrier cell simultaneously, promote transmembrane transport and suppress P-glycoprotein, slow release, effects such as cell compatibility is good, the transhipment of promotion lymph promote natural progesterone to absorb.Also available simultaneously short absorption and the strong chitosan of adhesiveness are further modified, so said preparation is a kind ofly to improve absorption and the new formulation of bioavailability of Progesterone after oral from multiple mechanism, a plurality of angle.
Description of drawings
accompanying drawing 1 amplifies 100,000 times transmission electron microscope picture for the natural progesterone proliposome preparation of prescription 1 of the present invention.
accompanying drawing 2 amplifies 100,000 times transmission electron microscope picture for blank liposome preparation of the present invention.
accompanying drawing 3 amplifies 10,000 times transmission electron microscope picture for the natural progesterone proliposome preparation of prescription 3 of the present invention.
accompanying drawing 4 amplifies 50,000 times transmission electron microscope picture for the natural progesterone proliposome preparation of prescription 3 of the present invention.
accompanying drawing 5 is the sem photograph of the natural progesterone proliposome preparation of prescription 1 of the present invention.
The transhipment curve chart that
accompanying drawing 6 Progesterone aqueous solution during for variable concentrations n=3 of the present invention and natural progesterone proliposome preparation are held at AP-BL end and BL-AP.
accompanying drawing 7 is the transport velocity of the P among the present invention at AP-BL end and BL-AP end.
accompanying drawing 8 is the transport velocity of the PL among the present invention at AP-BL end and BL-AP end.
(on behalf of P and PL, string diagram hold 2h to accumulate transhipment amount result from AP-BL to
accompanying drawing 9 cell during for the n=3 among the present invention to the picked-up of P and PL and AP-BL end accumulation transhipment amount result; Bar diagram is represented P and PL from AP-BL end 2h cell Chinese medicine intake result).
accompanying drawing 10 for before and after the drug treating among the present invention with the drug treating process in behind different time and the experiment end 12h cell stride the membrane resistance value.
accompanying drawing 11 for the rat oral gavage natural progesterone proliposome preparation (PL) among the present invention the blood drug level during with fine jade peaceful (QN) back n=6 through the time change curve.
Behind
accompanying drawing 12 tail intravenously administrable during for peaceful (QN) n=5 of rat natural progesterone proliposome preparation (PL) among the present invention and fine jade average blood drug level through the time curve chart.
accompanying drawing 13 for the blood drug level average of the rats'liver introportal infusion natural progesterone proliposome preparation (PL) among the present invention through the time curve chart.
The specific embodiment
the present invention does not receive the restriction of following embodiment, can confirm concrete embodiment according to technical scheme of the present invention and practical situation.
embodiment 3, this natural progesterone proliposome preparation: percent contains Progesterone 30% by weight; Phosphatidase 11 0%; 1 of surplus, the 2-propylene glycol is or/and PEG-400.
embodiment 7, this natural progesterone proliposome preparation: percent contains Progesterone 15% by weight; Phosphatidase 13 0%; 1 of surplus, the 2-propylene glycol is or/and PEG-400.
embodiment 9, this natural progesterone proliposome preparation: percent contains Progesterone 25% by weight; Phosphatidase 11 0%; 1 of surplus, the 2-propylene glycol is or/and PEG-400.
are in embodiment 1 to 10: 1, and the volume ratio of 2-propylene glycol and PEG-400 is 2: 1-3: 1; The concentration of Progesterone is 50 milligrams every milliliter; Phospholipid is oral soybean phospholipid or injection phospholipid or other synthetic phospholipid.
Natural progesterone proliposome preparation in
the foregoing description 1 to 10 has two kinds of methods for using: the one, and the natural progesterone proliposome preparation is directly oral; Be dispersed in the body fluid after in gastrointestinal tract, meeting body fluid, phospholipid hydration self assembly forms liposome; The 2nd,, at first the natural progesterone proliposome preparation is taken preceding thin up, be dispersed in the water after meeting with water, self assembly forms liposome, and then oral.The invention provides a kind of natural progesterone proliposome preparation; This natural progesterone proliposome preparation; It is a kind of oral formulations; Administration is more convenient than intramuscular injection, and patient's compliance is high, and said preparation is with multiple mechanism, solves problems such as enzymatic degradation and the bioavailability of Progesterone after oral is low from a plurality of angles.The present invention is dissolved in hydrophilic nonaqueous solvent propylene glycol or/and among the PEG-400 with natural progesterone and phospholipid; Form a kind of anhydrous solution; In this anhydrous solution gets into body or external add the water hydration after, the phospholipid in the solution can spontaneously align in water, forms the structure of the phospholipid bilayer of liposome; Simultaneously natural progesterone is encapsulated in the phospholipid bilayer film, self assembly forms liposome.The present invention carries out on the basis of a kind of liposome preparation technology that obtains license that the inventor proposes, and this patent name is " novel proliposome preparation and production method thereof and a method for using ", and the patent No. is ZL200410045430.1.But the present invention improves on the basis of aforementioned invention, and is directed against the oral problem of Progesterone, and from multiple mechanism, a plurality of angles improve its oral artifact availability, realizes the feasibility of preparation oral.
at first; This natural progesterone proliposome preparation makes full use of the package action of the lipoids bilayer of liposome; To avoid Progesterone, reduce its first pass effect, thereby improve the bioavailability of Progesterone in vivo by enzymatic degradation.Simultaneously liposome also have slow release, good with the histiocyte compatibility, reduce effects such as drug toxicity, also help improving the feasibility of the oral administration of natural progesterone.
Secondly
show according to research, and during oral liposome, liposome can pass through in gastrointestinal tract: 1. it is mobile to increase the gastrointestinal biomembrane, promotes the medicine transmembrane transport; 2. open cell and closely connect, promote intercellular transport; 3. suppress the P-glycoprotein, reduce medicine and efflux effect, increase the transmembrane transport of medicine; 4. the lipid membrane packaging medicine is avoided the gastrointestinal tract metabolism; 5. promote several kinds of modes of lymph transhipment to promote the transhipment of oral drugs gastrointestinal tract to absorb; Thereby effectively improve the particularly bioavailability of water-insoluble oral drugs of oral drugs, many medicines such as ciclosporin, fatsoluble vitamin etc. have confirmed these characteristics of liposome.And the present invention utilizes the These characteristics of liposome just, and natural progesterone is processed proliposome preparation, but said preparation meet in vivo after oral water or external add the water hydration after self assembly form the natural progesterone liposome; In gastrointestinal tract; Utilize liposome to open intercellular and connect, promote the transmembrane transport in the medicine gastrointestinal tract, promote the lymph transhipment; Reduce first-pass effect, improve the bioavailability of natural progesterone.Show according to research in addition; Progesterone is a P-glycoprotein substrate; And the P-glycoprotein can make the medicine that has absorbed be pumped back in the enteric cavity, thereby drug absorption is reduced, and the present invention has also utilized the lipid physical ability to suppress the effect of P-glycoprotein; Reduce medicine and efflux effect, improve the absorption and the bioavailability of Progesterone.
once more, the Progesterone water solublity is less, and dissolubility is merely 2mg/L in 37 ℃ of water.And the present invention has adopted hydrophilic nonaqueous solvent propylene glycol or/and PEG-400, utilizes the hydrophilic of solvent, improves the dissolution velocity of Progesterone, thereby promotes Progesterone to absorb.Improve oral administration biaavailability.
once more, the present invention further simplifies prescription on the basis of inventor's aforementioned patent (patent No. is ZL200410045430.1); Removed additional materials such as surfactant, through Progesterone, phospholipid, 1, the 2-propylene glycol is or/and PEG-400 processes the natural progesterone proliposome preparation; Under anhydrous state, be dissolved into anhydrous clear and bright solution; After adding water, this solution can spontaneous dispersion self assembly form liposome equally in water, show the characteristics of liposome.Compare with last patent simultaneously, removed heavy dose of prolonged application and had toxic surfactant, further avoided the toxicity behind the preparation oral, but the effect of raising bioavailability does not become.
in addition, the present invention also further wraps up the liposome that forms with chitosan, forms modified liposome, to expect further to improve the natural progesterone oral administration biaavailability.Chitosan is a kind of natural cationic polymer, can interact with electronegative cell membrane in vivo, reduces intercellular substance; Increase the medicine intercellular transport, chitosan viscosity is strong simultaneously, can adhere to rete malpighii in vivo; Thereby the prolong drug gastrointestinal tract holdup time; Promote drug absorption, in pharmaceutics, chitosan often is used as absorption enhancer, adhesive agent, gel rubber material use.The present invention introduces chitosan for this reason, further wraps up liposome with chitosan, experiment showed, that it can further improve bioavailability in the body of natural progesterone after oral.
in sum, this natural progesterone proliposome preparation provided by the invention is a kind of oral formulations, it is more easy, feasible that injection is compared in administration.Preparation technology is simple, is easy to suitability for industrialized production.And this natural progesterone proliposome preparation is to promote Progesterone to absorb with multiple mechanism, a plurality of angle; Avoid the oral back of Progesterone by enzymatic degradation in the gastrointestinal tract to a certain extent; Reduce its first pass effect; Absorption and bioavailability after the raising Progesterone is oral really realize the feasibility that natural progesterone is oral.
Below in conjunction with representative example the present invention is done further argumentation:
The representative prescription of natural progesterone proliposome preparation of the present invention is following:
prescription 1: Progesterone 0.40 gram; Oral soybean phospholipid 8.00 grams; 2.00 milliliters of PEG-400; 6.00 milliliters of 1,2 propylene glycol.During preparation, Progesterone and phospholipid are joined 1, in the solvent of 2-propylene glycol and PEG-400, under anhydrous condition, mix, the temperature of heating and maintenance mixture makes mixture be dissolved into clear and bright anhydrous solution at 50 ℃ to 70 ℃; Obtain the natural progesterone proliposome preparation.During use: this natural progesterone proliposome preparation can be directly oral, is dispersed in the body fluid after meeting body fluid in vivo, is self-assembled into liposome; Perhaps, at first the natural progesterone proliposome preparation is taken preceding thin up, be dispersed in the water after meeting with water, be self-assembled into liposome, and then oral.
The prepared natural progesterone proliposome preparation of prescription 1 is pressed in
; After adding the water hydration; Under transmission electron microscope, observe the structure that is multilamellar liposome, adopting Ma Erwen particle size determination appearance to measure its particle diameter is 103.7nm, narrow particle size distribution; Zeta potential is-88.9mV that adopting the dextran gel column chromatography method to measure its envelop rate is 72.36 ± 11.69%.
prescription 2: Progesterone 0.40 gram; Oral soybean phospholipid 6.00 grams; 2.00 milliliters of PEG-400; 1,2 propylene glycol 6.00mL milliliter.During preparation, Progesterone and phospholipid are joined 1, in the solvent of 2-propylene glycol and PEG-400, under anhydrous condition, mix, the temperature of heating and maintenance mixture makes mixture be dissolved into clear and bright anhydrous solution at 50 ℃ to 70 ℃; Obtain the natural progesterone proliposome preparation.During use: this natural progesterone pro-liposome can be directly oral, is dispersed in the body fluid after meeting body fluid in vivo, is self-assembled into liposome; Perhaps, at first the natural progesterone proliposome preparation is taken preceding thin up, be dispersed in the water after meeting with water, be self-assembled into liposome, and then oral.
The prepared natural progesterone proliposome preparation of prescription 2 is pressed in
, after adding the water hydration, under transmission electron microscope, observes the structure that is multilamellar liposome, and adopting the dextran gel column chromatography method to measure its envelop rate is 49.67 ± 9.24%.
prescription 3: Progesterone 0.40 gram; Oral soybean phospholipid 8.00 grams; 2.00 milliliters of PEG-400; 6.00 milliliters of 1,2 propylene glycol; 20 milliliters of 0.1% chitosan solutions.During preparation, the first step: chitosan is dissolved in the solution that is made into 1% (gram/milliliter) concentration in 0.3% (milliliter/milliliter) glacial acetic acid,, obtains the chitosan solution of 0.1% (gram/milliliter) again with solution dilution to 0.1%; Second step: Progesterone and phospholipid are joined 1, in the solvent of 2-propylene glycol and PEG-400, under anhydrous condition, mix, the temperature of heating and maintenance mixture makes mixture be dissolved into clear and bright anhydrous solution at 60 ℃; Getting 1.0 milliliters of this clear and bright anhydrous solutions adds 20 milliliters of mixings of water and gets liposome turbid liquor; Get in the chitosan solution that 5.0 milliliters of this liposome turbid liquors slowly are added dropwise to 20.0 milliliter 0.1%; Room temperature vibration 1.5-2.5 hour obtains the natural progesterone proliposome preparation.During use: this natural progesterone proliposome preparation can be directly oral, is dispersed in the body fluid after meeting body fluid in vivo, is self-assembled into liposome; Perhaps, at first the natural progesterone proliposome preparation is taken preceding thin up, be dispersed in the water after meeting with water, be self-assembled into liposome, and then oral.
The prepared natural progesterone proliposome preparation of prescription 3 is pressed in
; Under transmission electron microscope, observe the structure that is multilamellar liposome; Behind 500 times of the dilute with waters; Adopting Ma Erwen particle size determination appearance to measure its particle diameter is 83.74nm, and zeta potential is 48.1mv, and adopting its envelop rate of centrifugal determination is 78.53 ± 2.79%.
Embodiments of the invention checking result:
The transmission electron microscope and the scanning electron microscope result of
1, natural progesterone proliposome preparation.
get by prescription 1 prepared natural progesterone proliposome preparation an amount of; Point sample is on copper mesh; Use the phosphotungstic acid negative staining; Observe down in transmission electron microscope and to see Fig. 1, get the blank liposome preparation that makes with method simultaneously and observe down in transmission electron microscope and see Fig. 2, the natural progesterone proliposome preparation that makes by prescription 3 is handled the back with method and is observed down in transmission electron microscope and see Fig. 3 and Fig. 4; Other gets the natural progesterone proliposome preparation that makes by prescription 1 and sees Fig. 5 with the scanning electron microscopic observation formalness in right amount.
can be known by the scanning electron microscope result; The outside structure spherical in shape of the natural progesterone proliposome preparation that makes by prescription 1; TEM results can be known; The natural progesterone proliposome preparation that makes by prescription 1 is the multilamellar liposome form; The blank liposome preparation compares with the natural progesterone proliposome preparation that makes by prescription 1, can find obviously that high amount of drug is wrapped in the liposome or at surface of liposome, and this this method of explanation can be sealed the Progesterone medicine well.The natural progesterone proliposome preparation transmission electron microscope photo that makes by prescription 3 shows that the fingerprint characteristic of surface of liposome disappears behind the chitosan parcel, through 50,000 times of amplifications, assembles the winding state it is thus clear that surface of liposome has chain molecule to be.Show that liposome is wrapped up by chitosan effectively.
, press the study on the stability of prescription 1 prepared natural progesterone proliposome preparation
with reference to 2005 editions pharmacopeia accelerated tests methods, (lot number is respectively 20060327-1,20060327-2 to prepare three batches of natural progesterone proliposome preparations; 20060327-3), place the penicillin bottle to seal, be placed on temperature (40 ± 2 ℃); Following 6 months of the condition of relative humidity (75 ± 5) % respectively at sampling in 0,1,2,3,6 month, is measured medicament contg, envelop rate, the particle diameter of natural progesterone proliposome preparation; Observe its outward appearance, and with 0 day relatively, see table 1; The natural progesterone proliposome preparation is after placing 6 months as a result, and content, particle diameter have no significant change, and envelop rate raises after 6 months on the contrary to some extent; Color is deepened gradually; The content, the particle diameter that show accelerated tests condition held natural progesterone proliposome preparation after 6 months do not change, but phospholipid oxidation to some extent, prompting natural progesterone proliposome preparation should be preserved at shady and cool dry place.
, envelop rate and the percolation ratio of pressing prescription 1 prepared natural progesterone proliposome preparation measure
Three batches of natural progesterone proliposome preparations are got in
; Make natural progesterone proliposome preparation suspension after adding the water hydration respectively; Adopt the polydextran gel column chromatography to measure the envelop rate of three batches of natural progesterone proliposome preparations, the result sees table 2.And with after the natural progesterone proliposome preparation employing extension rate hydration in 1: 20; In room temperature and 4 ℃ of placements; Respectively at the envelop rate of measuring the natural progesterone proliposome preparation in 0,2,3,5,7 day; To leak into the ratio of medication amount and initial natural progesterone proliposome preparation Chinese medicine amount in the medium behind the different time, calculate percolation ratio, the result sees table 3.The result can know; 4 ℃ of following natural progesterone proliposome preparation percolation ratios than little under the room temperature; Natural progesterone proliposome preparation Chinese medicine amount can keep 71.06% of former medication amount basically after 7 days; The natural progesterone proliposome preparation just reached 26.30 ± 0.98% at 2 days with interior percolation ratio under the room temperature, and percolation ratio changed later on not quite at 2 days when room temperature was placed, and this possibly be because burst effect has taken place initial stage natural progesterone proliposome preparation; And the natural progesterone proliposome preparation does not see that 4 ℃ of held burst effect exists, and above presentation of results natural progesterone proliposome preparation is more stable under 4 ℃ of refrigerated conditions.
, the external absorption experiment of pressing prescription 1 prepared natural progesterone proliposome preparation
The Caco-2 cell model has been set up in
, the absorption and transport from cellular level research natural progesterone proliposome preparation after oral.Get and be cultured to the intact TransweLL film of 18-21d cell growthform; Inhale before the test and remove culture fluid; Behind 37 ℃ of cultivations of blank pH7.4 D-Hanks isosmotic solution 20min; Clean three times the impurity on flush away cell monolayer surface, the transhipment of holding the BasoLateraL end for ApicaL gently with D-Hanks liquid; The Progesterone aqueous solution or the natural progesterone proliposome preparation of 1.5mL variable concentrations are added to the ApicaL end as supplying with liquid, and the blank pH7.4D-Hanks liquid that while BasoLateraL end adding 2.6mL contains 4% hyclone is as receiving liquid; For the transhipment of holding the ApicaL end from BasoLateraL; The Progesterone aqueous solution or the natural progesterone proliposome preparation of 2.6mL variable concentrations are added to the BasoLateraL end as supplying with liquid, and the blank D-hanks liquid that while ApicaL end adding 1.5mL contains 4% hyclone is as receiving liquid.The TransweLL film is put in 37 ℃ of constant-temperature shaking tanks that rotating speed is 50rpm, respectively at 5,10,20,30,45,60,90,120min draws 0.1mL and receive liquid, adds 0.1mL37 ℃ of blank pH7.4 D-Hanks liquid that contains 4% hyclone simultaneously.After receiving liquid 100 μ L adding methanol 100 μ L, vortex mixes makes dissolving, and the centrifugal 15min of 12000rpm gets supernatant and measures content according to content assaying method.Calculate the transport of drug amount.The accumulation transhipment result of medicine in 2h sees shown in Figure 6 as a result.
can be known by figure; The accumulation transhipment amount of natural progesterone proliposome preparation is all apparently higher than the Progesterone aqueous solution on the both direction; Show that the natural progesterone proliposome preparation can obviously promote transport of drug, indicate that it can promote drug absorption in vivo.
Map to the time with accumulation transhipment amount
, tries to achieve dQ/dt, and (dt * A) tries to achieve transport of drug speed, and with transport velocity concentration is mapped, and sees Fig. 7 and Fig. 8 to utilize formula J=dQ/.
result show; The natural progesterone proliposome preparation be absorbed in low concentration the time have saturated trend; And natural progesterone proliposome preparation absorption rate is linear with concentration and increases during high concentration; Show that Progesterone processes the transporting mechanism that has changed Progesterone behind the liposome, make the Progesterone liposome mainly with passive diffusion way transhipment.Utilize the Papp computing formula to calculate apparent infiltration coefficient (Papp), the result sees table 4, table 5.The result finds that P changes with concentration change at the apparent infiltration coefficient of both direction; Show that it absorbs and secretion process all exists concentration dependent and saturability; All receive the adjusting of certain carrier protein; Wherein the Papp of BL-AP end is greater than the Papp value of AP-BL end, and prompting AP-BL end possibly exist the P-glycoprotein to efflux mechanism; Through calculating the ratio R of both direction Papp value; Discovery is along with PL concentration increases, and the R value levels off to 1 gradually, and PL absorption and secretion do not have concentration dependent when being illustrated in high concentration; The characteristic that meets passive diffusion; And the apparent infiltration coefficient of PL has concentration dependent during low concentration, and when showing low concentration, the PL transhipment receives certain carrier protein mediation.
are relatively found the accumulation transhipment amount and the apparent infiltration coefficient of Progesterone liposome and Progesterone; Accumulation transhipment amount that the Progesterone liposome is held at AP-BL end and BL-AP and apparent infiltration coefficient be all apparently higher than Progesterone, shows that Progesterone processes the absorption and the secretion that can promote Progesterone behind the liposome.
The picked-up situation of cell to the P solution and the PL of variable concentrations measured in
, and P and PL all can detect medicament contg in the cell in transport process as a result; See Fig. 9; Show that P and PL all can transport through approach in the born of the same parents, with intake with compare discovery with PL in the accumulation transhipment amount result of 2h with concentration P, PL is added to AP end; Its accumulation transhipment amount is high behind the 2h, and ingestion of drugs is few in the cell; P is added to the AP end, and its accumulation transhipment amount is low behind the 2h, and as if the ingestion of drugs amount is many in the cell, shows that PL can impel medicine to pass cell to the transhipment of BL end.
Figure 10 is seen with the P of concentration and PL the influence of striding membrane resistance (TEER) of Caco-2 cell is compared in
.After can knowing P and PL effect the membrane resistance value of striding of cell is descended; Both zero differences of decline degree, prompting P can closely be connected cell with PL to be opened, through the other approach transhipment of born of the same parents; Also point out medicine possibly have slight toxicity, can destroy cell integrity.After removing medicine and recovering cell culture 12h, the striding the membrane resistance value and can recover again of cell, the destruction that the medicine pair cell is described is temporary transient.
comprehensive above presentation of results Progesterone liposome maybe be through promotion Progesterone transmembrane transport, open cell closely connects, and through intercellular transport, thereby has promoted the absorption of Progesterone.
, the relative bioavailability of pressing prescription 1 prepared natural progesterone proliposome preparation measures
make the natural progesterone proliposome preparation by prescription 1; And with commercially available micronization Progesterone soft gelatin capsule (the trade name fine jade is peaceful; Qining QN) relatively, investigates liposome and whether can improve natural progesterone in the intravital bioavailability of rat.
Experimental technique
Get anovarism Wistar rat (fasting can't help more than the water 12h) in order after 6 jugular vein intubation; Be divided into two groups of A, B at random, 3 every group, wherein the A group is pressed 54mg/kg dosage; Smart title natural progesterone proliposome preparation is a certain amount of, gastric infusion behind the thin up; B group press 54mg/kg dosage, get commercially available micronization Progesterone soft gelatin capsule (the trade name fine jade is peaceful, Qining, QN) one, the taking-up content is dissolved in 1, is made into 5mgmL in the 2-propylene glycol
-1
Gastric infusion was as matched group after solution, draw solution added water.Irritate behind the stomach respectively at 0,5,10,20min and 0.5,1,2,4,6,8,12,24h get blood 0.5mL in centrifuge tube from the jugular vein conduit; The centrifugal 30min of 3000rpm behind the placement 1-2h; Separation of serum is got 50 μ L and is measured blood drug level according to radioimmunoassay method.The back intersection administration of one week is measured blood drug level with method.
Data processing method
adopt the 3p97 program software to carry out date processing respectively by compartment model and statistical moment method.
Pharmacokinetics result
Blood drug level during
natural progesterone proliposome preparation group deduction zero after the concentration through the time curve shown in figure 11.The blood drug level that natural progesterone proliposome preparation group and fine jade are rather organized each time point matches the t-check, the result show natural progesterone proliposome preparation group and fine jade rather organize blood drug level variant when 10min, 0.5h, 4h (
P＜0.05).Natural progesterone proliposome preparation group reaches peak concentration C
Max Obviously rather organize greater than fine jade.
With blood drug level through the time change through 3P97 pharmacokinetics routine processes, with AIC minimum principle and R
2
Maximum principle is confirmed compartment model, confirms that finally natural progesterone proliposome preparation and the peaceful physiological disposition of fine jade all meet two-compartment model, and weight is 1/C
2
Adopt two-compartment model, with weight 1/C
2
Carry out pharmacokinetic parameters and extract, adopt statistical moment to calculate AUC
0-inifinite
And MRT, the result sees table 6.
result can know that natural progesterone proliposome preparation group is rather compared with fine jade, and the natural progesterone proliposome preparation absorbs and increases, and can promote the gastrointestinal absorption of medicine; Elimination rate constant and medicine clearance rate reduce, and area increases under the absorption curve, and average residence time prolongs in the body, thus show the Progesterone liposome through promote to absorb, time of staying in the extension body, thereby improved the bioavailability after Progesterone is oral.Calculate according to the relative bioavailability formula: F
ReLative bioavailability
=AUC
PL
/ AUC
QN
Relative bioavailability F=(109.3/37.8) * 100%=289.19% as a result
show that the natural progesterone proliposome preparation compares with commercially available micronization Progesterone soft gelatin capsule (the trade name fine jade is peaceful), and bioavailability increases by 2.89 times in the body of Progesterone.
, the first pass effect of pressing prescription 1 prepared natural progesterone proliposome preparation measures
make the natural progesterone proliposome preparation by prescription 1, investigate liposome and whether can avoid the natural progesterone internal metabolism, reduce its first pass effect.
The tail intravenously administrable
are got the Wistar rat of having extractd ovary in order, after 5 jugular vein intubation at random; Press 18mg/kg dosage tail vein injection natural progesterone proliposome preparation; Respectively at 0,10,20min and 0.5,1,2,3,4,6,8,12,24h regularly get blood 0.5mL from conduit; The centrifugal 30min of 3000rpm/min behind placement 1～2h, separation of serum, the accurate 50 μ L that draw measure blood drug level with radioimmunoassay method.Get simultaneously 5 anovarism Wistar rats that the jugular vein post-operative conditions is good in addition, peaceful by same dosage tail vein injection fine jade, handle the back with method and measure blood drug level in the rat body.
The hepatic portal vein administration
are got the Wistar rat of having extractd ovary in order, after 6 jugular vein intubation at random; Behind the etherization, open the abdominal cavity, slowly inject the natural progesterone proliposome preparation by 18mg/kg dosage in hepatic portal vein; Carrying out abdominal part then fast sews up; Keep the animal waking state subsequently, simultaneously respectively at 0,10,20min and 0.5,1,2,4,6,8,12h regularly get blood 0.5mL from the jugular vein conduit, places the centrifugal 30min of 3000rpm behind 1～2h; Separation of serum, the accurate 50 μ L of absorption adopt radioimmunoassay method to measure blood drug level.
Experimental result
6.3.1 tail intravenously administrable
Natural progesterone proliposome preparation group and fine jade rather organize blood drug level through the time curve see shown in Figure 12, to blood drug level through the time curve carry out the model match, with AIC minimum and R
2
Maximum principle confirms that natural progesterone proliposome preparation and fine jade rather all meet two-compartment model, and weight is 1/C
2
, pharmacokinetic parameters is extracted, adopt statistical moment to calculate AUC
0-inifinite
And MRT, the result sees table 7.
Pharmacokinetic parameters is compared, and the peaceful group of natural progesterone proliposome preparation group and fine jade is compared as a result, AUC significantly increase (
P＜0.05), elimination rate constant K
10
Obviously reduce (
P＜0.05), in the body clearance rate CL obviously reduce (
P＜0.05), apparent volume of distribution V significantly reduce (
P＜0.05), show that the natural progesterone proliposome preparation rather compares with fine jade, can significantly improve bioavailability of medicament, reduce the clearance rate of medicine in blood, prolong drug is the time of staying in blood.
The hepatic portal vein administration
fine jade is an oil solution because of content rather, although go out content with propylene glycol extraction, but still has a small amount of oil droplet, so metabolism is slowed down after causing the hepatic portal vein administration, the physiological disposition error is bigger, does not therefore carry out the peaceful hepatic portal vein administration of fine jade.After the administration of natural progesterone proliposome preparation group in the rat body average blood drug level through the time curve see Figure 13.
To blood drug level through the time curve carry out the model match, confirm that natural progesterone proliposome preparation group meets two-compartment model, weight is 1/C
2
, pharmacokinetic parameters is extracted, adopt statistical moment to calculate AUC and MRT, the result sees table 8.
The bioavailability of different way of administration relatively
Rat through irritate stomach, hepatic portal vein and tail vein give natural progesterone proliposome preparation and fine jade peaceful after, the AUC of each route of administration
0-infinite
Value and bioavailability result of calculation are seen shown in the table 9.
result show, behind the rat oral gavage natural progesterone proliposome preparation, and absolute bioavailability F=24.51%, after the injection of rat THPV gives the natural progesterone proliposome preparation, bioavailability F=50.51%.It is thus clear that after rat gave the natural progesterone proliposome preparation, under experiment condition, by metabolism, about 26.00% liposome was by the gastrointestinal tract metabolism when head crosses liver for about 49.49% natural progesterone proliposome preparation.The result takes all factors into consideration to first pass effect, and AUC is rather big than fine jade for natural progesterone proliposome preparation oral route, and it is bigger to explain that drug absorption in the liposome is gone into the amount of blood; And can know by the experimental result of hepatic portal vein administration; The natural progesterone proliposome preparation still exists certain liver first-pass effect under the oral route; But because the Progesterone liposome has promoted the gastrointestinal absorption of medicine; Increased the degree of absorption of medicine, thus its oral artifact availability to be significantly higher than fine jade peaceful.
The bioavailability and the first pass effect result of
integrated natural Progesterone proliposome preparation; The natural progesterone proliposome preparation is rather compared with fine jade; Behind the oral administration, elimination speed is slower in the Progesterone liposome body, and clearance rate reduces; The time of staying of prolong drug in blood, relative bioavailability improves 2.89 times.After this proves that fully Progesterone is processed the natural progesterone proliposome preparation; The Progesterone liposome can promote drug absorption in vivo; Reduce the gastrointestinal metabolism simultaneously, the time of staying of prolong drug in blood, thereby finally make the Progesterone liposome bioavailability be improved significantly.
, the relative bioavailability of pressing the natural progesterone proliposome preparation of prescription 3 preparation measures
will be by the natural progesterone proliposome preparation of prescription 3 preparations, and whether the bioavailability of investigating liposome is improved.
pick the female rats except that ovary postoperative Wistar; Do the intubate operation in jugular vein; Treat that rat recovered after one day; Get 5 Wistar rats (fasting can't help more than the water 12h) that the jugular vein post-operative conditions is good, press 18mg/kg dosage and irritate stomach natural progesterone proliposome preparation.Irritate before the stomach and irritate stomach after 5,10,20min and 0.5,1,2,4,6,8,12,24h get blood 0.5mL in centrifuge tube from conduit respectively; The centrifugal 30min of 3000r/min behind placement 1～2h; Separation of serum is got 50 μ L and is measured blood drug level according to radioimmunoassay method.Natural progesterone proliposome preparation blood drug level data after the concentration when deduction is zero are as shown in table 10.
The blood drug level data are through the match of 3P97 pharmacokinetics software, with AIC minimum principle and R
2
Maximum principle is confirmed compartment model.Adopting two-compartment model, weight is 1/C
2
Pharmacokinetic parameters is extracted, calculated AUC with the statistical moment method
0-infinite
Value and average residence time MRT are with pharmacokinetic parameters and natural progesterone proliposome preparation and the peaceful pharmacokinetic parameters usefulness of fine jade
tStatistical disposition is carried out in-check, and the result sees table 11.The natural progesterone proliposome preparation is rather compared with fine jade as a result, MRT and AUC all have significant difference (
P＜0.05), presses the natural progesterone proliposome preparation and the natural progesterone proliposome preparation of pressing prescription 1 preparation, the equal zero difference of pharmacokinetic parameters of prescription 3 preparations.Show by natural progesterone proliposome preparation and also can significantly improve its bioavailability, average residence time in the body of prolong drug by prescription 3 preparations.
with fine jade rather as reference preparation; Calculate the natural progesterone proliposome preparation that makes by prescription 1 and the relative bioavailability of the natural progesterone proliposome preparation that makes by prescription 3 by following formula; Again with the natural progesterone proliposome preparation that makes by prescription 1 as reference preparation; Calculate the relative bioavailability of the natural progesterone proliposome preparation that makes by prescription 3 by following formula, the result sees table 12.
×Dose
R
/AUC
R
×Dose
T
×100%
result shows peaceful with respect to fine jade; The relative bioavailability of the natural progesterone proliposome preparation that makes by prescription 3 improves 6.03 times; With respect to the natural progesterone proliposome preparation that makes by prescription 1, the natural progesterone proliposome preparation relative bioavailability that makes by prescription 3 improves 2.08 times.
The interior medicine dynamics result of the natural progesterone proliposome preparation that makes by prescription 3 shows; Its interior medicine dynamics process meets two-compartment model; Rather compare with fine jade, AUC obviously increases, and average residence time obviously prolongs; Calculate through the relative bioavailability value, relative bioavailability has reached 602.85%; Compare with the bioavailability of the natural progesterone proliposome preparation that makes by prescription 1, the bioavailability of the natural progesterone proliposome preparation that makes by prescription 3 improves 2.08 times,
above result fully shows the natural progesterone proliposome preparation that makes by prescription 3, can improve absorption characteristic in the body, further improves bioavailability in the corpus luteum ketoboidies.
are through above-mentioned evaluation; Explain that the present invention can successfully prepare the natural progesterone proliposome preparation; The natural progesterone proliposome preparation adds after the water hydration can spontaneous formation liposome; And the natural progesterone proliposome preparation that forms is the multilamellar liposome form, and mean diameter is 103.7nm, narrow particle size distribution, surperficial bear electricity, surface electrical place value can to reach under 72.36 ± 11.69%, 4 ℃ of placement conditions percolation ratio little for-88.9mv, envelop rate.The natural progesterone proliposome preparation is all responsive to illumination and temperature, should be stored in shady and cool dry place.Can pass through after the natural progesterone proliposome preparation is oral to promote the Progesterone transmembrane transport, thus the absorption that effectively improves Progesterone.Rather compare with fine jade, the natural progesterone proliposome preparation can prolong residence time in the corpus luteum ketoboidies, improves the Progesterone bioavailability.The natural progesterone proliposome preparation that makes by prescription 3 can make the liposome bioavailability further improve.
combine in the Progesterone clinical practice to need long term administration in the hormonal supplementation therapy particularly but the fact that lacks effective oral progesterone preparation; Progesterone is processed the natural progesterone proliposome preparation; Thereby through promoting Progesterone to absorb, avoid the Progesterone metabolism can improve the Progesterone bioavailability to a certain extent, this has certain feasibility and important meaning for exploitation Progesterone oral formulations.
Claims (7)
1. a natural progesterone proliposome preparation is characterized in that percent contains Progesterone 1% to 30% by weight; Phosphatidase 11 0% to 30%; 1 of surplus, the 2-propylene glycol is or/and PEG-400.
2. natural progesterone proliposome preparation according to claim 1 is characterized in that 1, and the volume ratio of 2-propylene glycol and PEG-400 is 2: 1-3: 1.
3. natural progesterone proliposome preparation according to claim 1 and 2, the concentration that it is characterized in that Progesterone are 50 milligrams every milliliter.
4. natural progesterone proliposome preparation according to claim 1 and 2 is characterized in that phospholipid is oral soybean phospholipid or injection phospholipid or other synthetic phospholipid.
5. natural progesterone proliposome preparation according to claim 3 is characterized in that phospholipid is oral soybean phospholipid or injection phospholipid or other synthetic phospholipid.
6. one kind according to claim 1 or 2 or 3 or the method for preparing of 4 or 5 described natural progesterone proliposome preparations; It is characterized in that being undertaken by following step: at first Progesterone and the phospholipid with requirement joins 1 of requirement; The 2-propylene glycol is or/and in the solvent of PEG-400; Under anhydrous condition, mix; The temperature of heating and maintenance mixture makes mixture be dissolved into clear and bright anhydrous solution and perhaps clear and bright anhydrous solution is further wrapped up with chitosan material or clear and bright anhydrous solution is wrapped in the capsule at 50 ℃ to 70 ℃, obtains the natural progesterone proliposome preparation.
7. one kind according to claim 1 or 2 or 3 or the method for using of 4 or 5 described natural progesterone proliposome preparations, it is characterized in that this natural progesterone proliposome preparation takes preceding thin up, and phospholipid hydration self assembly forms liposome.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105802999A (en) * | 2016-04-01 | 2016-07-27 | 中南大学湘雅医院 | Kit and method for transmembrane transport of ODNs by membrane protein ENTs |
| CN106063783A (en) * | 2016-06-16 | 2016-11-02 | 浙江爱生药业有限公司 | A kind of Progesterone slow-releasing microcapsule preparation and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1546043A (en) * | 2003-11-28 | 2004-11-17 | 北京工商大学 | Percutaneous formula of natural gestagen and its preparation |
| CN1698585A (en) * | 2004-05-19 | 2005-11-23 | 新疆维吾尔自治区包虫病临床研究所 | Prosoma liposome preparation, its production method and using method |
| CN102397255A (en) * | 2011-11-24 | 2012-04-04 | 广东药学院 | Progesterone ethosome, and preparation method and application thereof |
-
2012
- 2012-04-29 CN CN2012101307520A patent/CN102652733A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1546043A (en) * | 2003-11-28 | 2004-11-17 | 北京工商大学 | Percutaneous formula of natural gestagen and its preparation |
| CN1698585A (en) * | 2004-05-19 | 2005-11-23 | 新疆维吾尔自治区包虫病临床研究所 | Prosoma liposome preparation, its production method and using method |
| CN102397255A (en) * | 2011-11-24 | 2012-04-04 | 广东药学院 | Progesterone ethosome, and preparation method and application thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105802999A (en) * | 2016-04-01 | 2016-07-27 | 中南大学湘雅医院 | Kit and method for transmembrane transport of ODNs by membrane protein ENTs |
| CN105802999B (en) * | 2016-04-01 | 2019-05-03 | 中南大学湘雅医院 | Kit and method for transmembrane transport of ODNs by membrane protein ENTs |
| CN106063783A (en) * | 2016-06-16 | 2016-11-02 | 浙江爱生药业有限公司 | A kind of Progesterone slow-releasing microcapsule preparation and preparation method thereof |
| CN106063783B (en) * | 2016-06-16 | 2019-03-12 | 浙江爱生药业有限公司 | A kind of progesterone slow-releasing microcapsule preparation and preparation method thereof |
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