CN1446540A - Combination of semisolid framework preparation of progesterone - Google Patents

Abstract

The invention discloses a composition of progesterone semi-solid skeleton preparation. Its components and content include: 0.5-10 wt% of progesterone, 1-98.5 wt% of surfactant with HLB>12, and 1-98.5 wt% of semi-solid skeleton carrier. The composition of the progesterone semi-solid matrix preparation of the invention has good stripping properties, can significantly increase the concentration of progesterone in blood, and improve various symptoms and diseases caused by lack of progesterone or insufficient corpus luteum function. The bioavailability of the progesterone capsule dog of the present invention is 2.77 times that of the domestic progesterone injection. The progesterone capsule of the invention has the characteristics of low dosage and high bioavailability.

Description

The compositions of Progesterone semi-solid skeleton preparation

Technical field

The present invention relates to a kind of progesterone preparation.

Background technology

Progesterone, its English Progesterone by name, its chemistry pregnant steroid by name-4-alkene-3, the 20-diketone, its structural formula is as follows: Molecular formula: C ₂₁H ₃₀O ₂, molecular weight: 314.47.

Progesterone can significantly increase progestogen concentration in the blood, has the general action of progestogen.It acts on endometrium, can make the caused propagation phase of estrogen be converted into the secretory phase, for implantation of ovum and early stage embryo's nutrition provides advantage and keeps gestation.Improve various symptoms and disease that for want of progestogen or inadequate luteal function caused:

(1) cures mainly premenstrual syndrome and the miscarriage that luteal phase defect causes.

(2) because withdrawal bleeding is carried out in dysfunctional uterine hemorrhage due to the anovulation or amenorrhea etc.

(3) replenish the various diseases that CLI causes.

(4) use of the effect of the simple estrogen of antagonism with the estrogen cycle to inner membrance.

In addition, Progesterone also is used to improve the pregnancy rate of animal in veterinary drug.

But the Progesterone water solublity is very poor, oral post-absorption amount is few and very fast by the liver metabolism inactivation, therefore the dosage form of using clinically is injection, and is very inconvenient to patient especially life-time service person, and easily causes medicine to deposit partial musculature and cause lump pain etc.

In view of above situation, France has developed the oral micropowder soft gelatin capsule UTROGESTAN (Utrogestan) that gone on the market and has replaced injection.The Utrogestan soft gelatin capsule has improved the oral bioavailability of Progesterone to a certain extent, but costs an arm and a leg, and 8 yuan every, listing at home.Therefore, still there is not very good progesterone preparation at present.

Summary of the invention

The technical issues that need to address of the present invention are to disclose a kind of Progesterone semi-solid backbone type preparation (Semi Solid Matrix), promptly in medicinal liquid, add material with wax shape fusing point sample, energy hot melt when high temperature, it during room temperature solid, compare with traditional powder particle filling, it can avoid drug powder to fly upward (being particularly useful for hormone and anticarcinogen); Loadings is even, and principal agent dosage is accurate; Medicine or medicinal liquid are scattered in the excipient isolated with air and dampness, thereby more stable; Suitably adjust prescription, can obtain desired high bioavailability, in the hope of making pharmacological active substance Progesterone absorption in vivo better, the curative effect that obtains under lower dosage also reduces untoward reaction.

Preparation of the present invention comprises:

Progesterone 0.5～10% (weight)

The surfactant 1～98.5% (weight) of HLB (hydrophile-lipophile balance value) more than 12

The carrier 1～98.5% (weight) of semi-solid backbone

The surfactant that meets above-mentioned condition comprises the polyoxyethylene castor oil double glyceride, polyoxyethylene 6 sorbitan mono-laurates sorbitan fatty acid esters (span) such as (span 20s), polyoxyethylene mono laurate Pyrusussuriensis ester, polyoxyethylene fatty acid Pyrusussuriensis esters (tween) such as polyoxyethylene list oleic acid Pyrusussuriensis ester, polyoxyethylene alkyl ethers such as Brij30, cithrols such as polyoxyethylene 10 monolaurates, polyoxyethylene castor oil, certain herbaceous plants with big flowers acid glyceryl laurate ester, mixed fatty glycerides such as caproic acid glyceryl laurate ester, the sad capric acid polyethyleneglycol glyceride and the mixture of two or more compositions in them.

The carrier of used semi-solid backbone comprises one or more in Polyethylene Glycol, Myrj 52, poloxamer, polyoxyethylene sorbitan monostearate, 12～18 carbon fatty acid glyceride or propylene glycol stearate, the lauric acid polyethyleneglycol glyceride among the present invention.

The main effect of said surfactant is the hydrophilic that increases Progesterone, promotes its absorption in vivo, and its hydrophile-lipophile balance value HLB value is big more, and its hydrophilic is also big more, and effect is also just stronger.

So surfactant can increase the dissolubility of insoluble drug in water, be commonly considered as because surfactant forms micelle (micelle) result (Micelles) in water.Micelle is inwardly to form a minimum oil droplet (nonpolar center) by the lipophilic group of surfactant, hydrophilic group then outside (hydrophilic group of nonionic then from oil droplets as wavy to around stretch into aqueous phase) form spheroid.

Think that now micelle can insert solubilizate such as Progesterone in the oil droplet in the micelle with the nonpolar part of its molecule with polar molecule slightly, its polarity part then stretches between the hydrophilic group of the surfactant in the water and produces solubilization.

Surfactant has the effect of lipin dissolving when low concentration, can dissolve the phospholipid of gastrointestinal mucosal and change epithelial permeability, reduces the barrier action of intestinal mucosa lipoid.So many medicines that originally were difficult to absorb, add surfactant and make to absorb and increase by passive diffusion.Therefore the agent of HLB value higher surface activity can increase the dissolubility of Progesterone in water, can reduce the barrier action of intestinal mucosa lipoid again and increases its absorption in vivo.

Said semi-solid backbone carrier with substrate with certain HLB value for well, it has water solublity on the one hand, can be as the semisolid dispersion of poorly water soluble drugs, and certain liposoluble performance is arranged again, with can also form low-melting fused matter after Progesterone mixes, increase the medicine absorption in vivo.

Preparation of the present invention is preparation like this:

Each composition is quantitatively mixed according to the above ratio, stir, heating to make that preparation is easier to be carried out, and can be made into capsule with capsule liquid-filling machine (modular system is arranged) abroad, and also available miscellaneous equipment is made drop pill, powder etc.

Stability to the Progesterone semi-solid skeleton preparation that makes of the present invention is investigated:

This product is removed outer package directly exposed under illumination 4500LX, 40 ℃, 25 ℃ RH92.5% conditions each 10 days, carry out character, content color and luster, cracked property, dissolution, mensuration content, chromatograph inspection catabolite with the primary sample contrast, all basicly stable.

This product is under the listing terms of packing (mould bottled, aluminum plastic film seals), and room temperature was placed 6 months and 40 ℃ of RH75% conditions were quickened 6 months, and regularly investigated index observing mensuration by the quality standard of working out, and every index is all basicly stable.

Each constituent of this product is contrast with France's " Utrogestan " micropowder soft gelatin capsule, is that dissolution medium is measured dissolution with the distilled water, to show the superiority of each component:

Progesterone is made into the capsules As of 1% 4 kinds different prescriptions, B, C, D makes test sample, with France's " An Qitan " micropowder soft gelatin capsule content is contrast, carry out the dissolution test by second method in 2000 editions Chinese Pharmacopoeia appendix XC dissolution methods: measure the distilled water 300ml that handles through the degassing, inject in each process container, heat and make water remain on 37 ± 0.5 ℃, with test sample 5mg/ grain, put into 6 process containers respectively, startup rotation (50 rev/mins) immediately also picks up counting, during to 30 minutes, at the regulation sample point, draw solution is an amount of, and filters through 0.45 μ m microporous filter membrane immediately, gets subsequent filtrate and measures by spectrophotography, measure trap at 241nm wavelength place, press the absorptance (E of Progesterone _1cm ^1%) be 540 calculating, calculate each stripping percentage rate.

The stripping percentage rate of table 1 " An Qitan " micro powder capsules and each prescription (%, 30 minutes)

	An Qitan (content)	????A	????B	????C	????D
						????1	????0.75	??6.92	??29.68	??74.53	??52.00
????2	????0.33	??23.65	??42.62	??47.09	??41.95
						????3	????0.25	??12.72	??38.83	??74.76	??43.29
????4	????0.47	??22.54	??44.19	??58.47	??74.31
						????5	????0.38	??18.08	??33.70	??50.21	??80.34
????6	????0.45	??34.59	??34.81	??51.33	??70.29
						Average	????0.44	??19.75	??37.31	??59.40	??60.36
????±SD	????0.17	??9.59	??5.57	??12.38	??16.69

By in the table 1 as seen, France's " An Qitan " micropowder soft gelatin capsule and prescription A, B, C, D are in the time of 30 minutes, dissolution is respectively 0.44% ± 0.17,19.75% ± 9.59,37.31% ± 5.57,59.40% ± 12.38,60.36% ± 16.69.Illustrate that the stripping in distilled water of " An Qitan " micropowder soft gelatin capsule is very poor, prescription D is best, and the stripping percentage rate is 60.36% ± 16.69.Therefore selected prescription D is this product prescription (Utrogestan and the absolute stripping quantity of prescription D respectively are 0.44mg, 3.00mg).

Progesterone capsule animal relative bioavailability of the present invention experimental study:

This research is subjects with 6 of domesticated dogs, adopt consubstantiality cross matching method, single dose intersects and to irritate on an empty stomach that stomach gives 20 of progesterone capsules of the present invention (containing Progesterone 100mg) or intramuscular injection progesterone injection 10ml (contains Progesterone 100mg respectively, 10mg/ml * 10ml), adopt radioimmunoassay method different time blood plasma Chinese medicine concentration, according to blood drug level-time data, tried to achieve main pharmacokinetic parameter.

Result of calculation shows:

The T of Progesterone in the progesterone capsule of the present invention _MaxBe 0.62 ± 0.14 (h), C _MaxBe 193.08 ± 33.43 (ng/ml), t _{1/2 (ke)}Be 3.53 ± 0.50 (h), AUC _0-10Be 842.74 ± 109.20 (ng.h/ml), AUC _0-∞Be 964.87 ± 112.51 (ng.h/ml);

The T of Progesterone in the progesterone injection _MaxBe 0.29 ± 0.10 (h), C _MaxBe 119.06 ± 20.22 (ng/ml), t _{1/2 (ke)}Be 2.04 ± 0.59 (h), AUC _0-10Be 335.69 ± 77.31 (ng.h/ml), AUC _0-∞Be 373.18 ± 87.82 (ng.h/ml).

Concrete outcome sees Table 2, table 3, table 4.

Table 2 single dose gives the pharmacokinetic parameter behind the progesterone capsule of the present invention (T)

Ke????T _1/2(ke)????Tmax?????Cmax?????AUC _0-10?????AUC _0-∞

No

(h ^-1)???(h)?????????(h)????(ng/ml)??(ng·h/ml)??(ng·h/ml)

A??????0.18?????3.85????????0.75????148.39???704.00??????799.17

B??????0.18?????3.85????????0.5?????204.56???863.81??????1041.36

C??????0.18?????3.85????????0.5?????167.59???733.80??????866.08

D??????0.23?????3.01????????0.5?????241.97???844.65??????954.61

E??????0.18?????3.85????????0.75????211.61???917.53??????1079.36

F??????0.25?????2.77????????0.75????184.36???992.64??????1048.64

Mean???0.20?????3.53????????0.62????193.08???842.74??????964.87

SD?????0.032????0.50????????0.14????33.43????109.20??????112.51

Table 3 single dose gives the pharmacokinetic parameter behind the progesterone injection (R)

Ke???????T _1/2(ke)???Tmax?????Cmax?????AUC _0-10???AUC _0-∞

No

(h ^-1)????(h)?????????(h)?????(ng/ml)??(ng·h/ml)?(ng·h/ml)

A?????0.37??????1.87????????0.25????143.51????421.92????442.78

B?????0.48??????1.44????????0.25????116.80????225.16????229.91

C?????0.25??????2.77????????0.25????108.24????364.70????413.30

D?????0.25??????2.77????????0.25????102.07????276.62????363.79

E?????0.39??????1.78????????0.5?????99.28?????315.84????321.79

F?????0.44??????1.58????????0.25????144.44????409.92????467.31

Mean??0.36??????2.04????????0.29????119.06????335.69????373.18

SD????0.096?????0.59????????0.10????20.22?????77.31?????87.82

The relative bioavailability of table 4 progesterone capsule is calculated

AUC(ng·h/ml)

No

T???????????????R??????????????F(％)

A??????????799.17??????????442.78?????????180.49

B??????????1041.36?????????229.91?????????452.94

C??????????866.08??????????413.30?????????209.55

D??????????954.61??????????363.98?????????262.27

E??????????1079.36?????????321.79?????????335.42

F??????????1048.64?????????467.31?????????224.40

Mean???????964.87??????????373.18?????????277.53

SD?????????112.51??????????87.82??????????101.20

Adopt cross-over design method of analysis of variance, two-one sided test and (1-2 α) confidence interval method that above-mentioned main pharmacokinetic parameter is carried out statistical analysis and evaluation of bioequivalence, the result shows: by Cmax, Tmax and the AUC of Progesterone between test preparation and control formulation _0-∞Significant significant difference (P＜0.05) is all arranged, progesterone capsule of the present invention is 277.53 ± 101.20% to the average relative bioavailability F of progesterone injection, 90% of its bioavailability parameter value crediblely is limited to 234.20～512.16%, as seen two kinds of preparation bioavailability inequivalences, test preparation is than reference preparation bioavailability height.

The specific embodiment

Embodiment 1

With Progesterone 2 grams, polyoxyethylene castor oil double glyceride 25 grams, 73 gram Macrogol 4000s mix, and stir, and heating for dissolving is made 100 of capsules with the capsule liquid-filling machine, and Progesterone content is 0.02 gram/grain.

Embodiment 2

With Progesterone 3 grams, polyoxyethylene castor oil and certain herbaceous plants with big flowers acid glyceryl laurate ester mixture (1: 1, weight ratio) 24 grams, 73 gram ethylene glycol 6000 mix, and stir, and heating for dissolving is made 100 of capsules with the capsule liquid-filling machine, and Progesterone content is 0.03 gram/grain.

Embodiment 3

With Progesterone 3 grams, polyoxyethylene 6 sorbitan mono-laurates 24 grams, the mixture of Myrj 52 and ethylene glycol 6000 (1: 1, weight ratio) 73 grams mix, and stir heating for dissolving, make 100 of capsules with the capsule liquid-filling machine, Progesterone content is 0.03 gram/grain.

Claims (5)

1. A composition of progesterone semi-solid matrix preparation, characterized in that the components and content include: progesterone 0.5-10wt%, HLB>12 surfactant 1-98.5wt%, semi-solid matrix carrier 1 ~98.5 wt%. 2. The composition according to claim 1, wherein said surfactant comprises polyoxyethylene castor oil diglyceride, polyoxyethylene 6 sorbitan monolaurate (Span 20), Polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate, polyoxyethylene lauryl ether, polyoxyethylene 10 monolaurate, polyoxyethylene castor oil, glyceryl caprate laurate, lauryl caproate One or more of glyceryl caprylate or macrogol glyceride caprylate. 3. The composition according to claim 2, characterized in that said surfactants are glyceryl caprate laurate and polyoxyethylene sorbitan monolaurate, caprylic caprate macrogol glyceride. 4. The composition according to claim 1, characterized in that the carrier of said semi-solid skeleton comprises polyethylene glycol, polyoxyethylene 40 stearate, poloxamer, polyoxyethylene sorbitan One or more of monostearate, 12-18 carbon fatty acid glyceride or propylene glycol stearate, macrogol glyceryl laurate or macrogol glycerol monostearate. 5. The composition according to claim 4, characterized in that the carrier of the semi-solid skeleton is polyoxyethylene sorbitan monostearate, poloxamer, or fatty acid polyethylene glycol glyceride .