CN106349192A - Eutectic of orlistat and amino acid, and pharmaceutical composition comprising eutectic - Google Patents
Eutectic of orlistat and amino acid, and pharmaceutical composition comprising eutectic Download PDFInfo
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- CN106349192A CN106349192A CN201610884801.8A CN201610884801A CN106349192A CN 106349192 A CN106349192 A CN 106349192A CN 201610884801 A CN201610884801 A CN 201610884801A CN 106349192 A CN106349192 A CN 106349192A
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- orlistat
- eutectic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/10—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having one or more double bonds between ring members or between ring members and non-ring members
- C07D305/12—Beta-lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to eutectic of orlistat and amino acid, and a pharmaceutical composition comprising the eutectic. The eutectic formed by the orlistat, L-proline, L-leucine or L-valine according to an appropriate molar ratio has higher melting points, which are respectively 95.3 DEG C, 130.3 DEG C and 103.5 DEG C, and remarkably higher than type II orlistat in commercially available orlistat capsules, so that a drying process during a bulk pharmaceutical chemical preparation and preparation preparing process can be carried out at higher temperature, the drying time is shortened, the drying efficiency is improved, and the drying energy consumption is reduced. In addition, the obtained eutectic is used as a raw material for preparing a capsule agent, so that the dissolution rate of the orlistat in the obtained capsule agent is higher than the type II orlistat used in the commercially available orlistat capsules, and the orlistat in the obtained capsule agent takes effect more quickly than the type II orlistat used in the commercially available orlistat capsules.
Description
Technical field
The invention belongs to pharmaceutical technology field is and in particular to the eutectic of orlistat and aminoacid and comprise this eutectic
Pharmaceutical composition.
Background technology
Orlistat (orlistat) is to research and develop lipase inhibitor class appetrol, trade name by company of Roche Group
Xenical, eighties of last century late nineteen nineties take the lead in American-European listing, and calendar year 2001 is in Discussion on Chinese Listed, and is eaten by China in 2005
The approval of product Drug Administration switchs to nonprescription drugss.[(2s, 3s) 3- is own for its chemical entitled n- formyl-l- leucine (s) -1
Base -4 epoxide -2- glycidyl methyl] ten diester, also referred to as ORLISTAT (tetrahydrolipstatin, thl) they are a kind of
Semisynthetic lipstatin derivant, its chemical structural formula is as shown below:
Orlistat with the capsule of its crystal formation and tablet hyoscine, be also at present both at home and abroad uniquely one kind do not affect to eat
It is intended to, do not act on the chemical appetrol of central nervous system, security features are superior.Type orlistat knot in commercial preparation
Crystalline substance to pale white crystals powder, is substantially insoluble in water, is soluble in chloroform, be highly soluble in methanol and ethanol, and giving birth to for white
No pka value in the range of reason ph value.At present, domestic production orlistat has two methods: one kind is chemical complete synthesis, reactions steps
Many, yield is low, and environment compatibility is poor；Another kind is that fermentable obtains orlistat intermediate, and then intermediate is through a step
Hydrogenation synthesis orlistat, the orlistat that second method produces is occupied an leading position.No matter which kind of method, is required for last
The orlistat of one step chemical reaction gained is dried, to remove moisture and organic solvent in product.And crystal formation Ao Lisi
His fusing point is only 43 DEG C, thus needing to temperature and time is given in crude drug and finished dosage form dry run with strict control
System.
The low melting point of orlistat and dissolubility difference directly limit its application, and fusing point and dissolubility often with material
Crystal formation is relevant.In prior art, the research with regard to orlistat crystal formation has: international monopoly wo2005026140 disclose type with
The preparation method of type orlistat, and the characteristic parameter collection of illustrative plates of two kinds of crystal formations, such as x-ray diffraction (xrd) collection of illustrative plates, differential scanning
Calorimetric (dsc) collection of illustrative plates and infrared analysiss (ir) collection of illustrative plates.Separately have, international monopoly wo2010084502 discloses a kind of orlistat knot
Crystalline form and its xrd and ir characteristic parameter, this crystallization is in polar solvent and non-polar organic solvent by solid orlistat
Recrystallization in mixed system and obtain, the preferred acetone-heptane system of described solvent mixed system, but undisclosed mixed in this patent
Various solvent proportions in fit system, whether the other structures feature also gained orlistat crystal form being not disclosed (is molten
Agent compound) and pharmacologically active parameter.Additionally, international monopoly wo2003047531 also discloses type and the type of orlistat
Crystal form, and the preparation side of the xrd collection of illustrative plates, thermogravimetric analysiss (tga) collection of illustrative plates and dsc collection of illustrative plates, crystallization of both crystal forms
Method and the solid preparation containing this two kinds of crystal forms, but undisclosed reactive dyes, do not disclose this two kinds of crystal forms and the world
What advantage orlistat type disclosed in patent wo2005026140 and type have compared.
Eutectic refers to that active constituents of medicine (active pharmaceutical ingredient, api) and eutectic are formed
The crystal that thing (cocrystal former, ccf) is combined in the presence of hydrogen bond or other non-covalent bonds, wherein api with
Ccf is between solid, and each component at room temperature in pure state has fixing stoichiometric proportion.After api forms eutectic, permissible
Fusing point, draw moist, stability, dissolubility and dissolution, bioavailability, bioavailability, release, mechanical performance etc. are many
Aspect all can make moderate progress, and therefore eutectic theory has broad application prospects in new drug research field.
Currently without with regard to preparing eutectic formation using orlistat and aminoacid, to overcome orlistat to there is fusing point
The relevant report of the poor defect of low, dissolubility.
Content of the invention
For solving technical problem present in prior art, it is an object of the invention to provide a kind of orlistat and amino
Acid eutectic and comprise this eutectiferous pharmaceutical composition.Described eutectic has higher fusing point, it is possible to decrease crude drug
With the requirement to drying condition in the preparation process of preparation, and there is higher dissolution, accelerate drug effect.
The present invention is by following technical solution to be attained in that
On the one hand, with fusing point and melting range as index, having investigated will be multiple normal using conventional eutectic preparation method for the present invention
The aminoacid seen and orlistat are prepared into eutectiferous probability, described eutectic preparation method be medicinal chemistry art institute
Preparation method (the chemistry with regard to pharmaceutical co-crystals that the method known, such as Gao Yuan et al. disclose in " pharmaceutical co-crystals progress "
Progress, 2010,05:829-836), it is incorporated herein by quoting.It was found that it is potential common in the amino acidses accepting to investigate
In brilliant formation, only l- leucine, l- L-Valine, l- proline can adopt cooling crystallize method and Ao Lisi in different solvents
He forms the crystalline material of melting range narrow (< 1 DEG C), illustrates to define single pure substance.
On the other hand, the present invention be respectively adopted nuclear magnetic resonance, NMR (1H-nmr), Powder x-ray diffraction (xrpd), differential scanning
The eutectic that calorimetry (dsc), thermogravimetric analysiss (tga) are formed to orlistat and above-mentioned eutectic formation has carried out structural table
Levy, thus further demonstrate that the formation of eutectic.
Based on this, the present invention provides a kind of orlistat and aminoacid eutectic, and described aminoacid is selected from: l- dried meat ammonia
One of acid, l- leucine or l- L-Valine.
Further, described orlistat and l- proline form eutectic with the mol ratio of 1:1.
Further, described orlistat and l- leucine form eutectic with the mol ratio of 1:1.
Further, described orlistat and l- L-Valine form eutectic with the mol ratio of 3:2.
Further, described orlistat and l- proline eutectiferous x- ray powder diffraction pattern 19.2 °,
There is characteristic absorption peak at 22.6 °, 25.0 ° and 27.1 ° of 2 θ ± 0.2 ° 2 θ angle.
Further, described orlistat and l- leucine eutectiferous x- ray powder diffraction pattern 9.4 °,
There is characteristic absorption peak at 18.5 °, 19.3 °, 24.9 ° and 27.0 ° of 2 θ ± 0.2 ° 2 θ angle.
Further, described orlistat and l- L-Valine eutectiferous x- ray powder diffraction pattern 19.0 °,
There is characteristic absorption peak at 19.3 °, 22.4 °, 24.9 °, 27.1 ° and 27.8 ° of 2 θ ± 0.2 ° 2 θ angle.
Moreover, it relates to a kind of contain described eutectiferous pharmaceutical composition, this pharmaceutical composition is oral solid
Body preparation, with orlistat l- proline eutectic, orlistat l- leucine eutectic, orlistat l- L-Valine eutectic
In at least one as effective ingredient, be equipped with pharmaceutically acceptable additive and be prepared from.Described additive does not change substantially
Become orlistat and amino acids formed eutectic, also with any composition in pharmaceutical composition any effect will not occur and with
Orlistat aminoacid eutectic used is incompatible.
Described oral solid formulation is prepared by method known in field of pharmaceutical preparations, for example, with reference to Cui Fude
Chief editor, " pharmaceuticss " (the 7th edition) (People's Health Publisher's publication).Specifically, can by 1:1 orlistat l- proline altogether
Crystalline substance, 1:1 orlistat l- leucine eutectic or 3:2 orlistat l- L-Valine eutectic and at least one pharmaceutically acceptable tax
Shape agent phase mixes, and described excipient can be citric acid or dicalcium phosphate, or is (a) filler or extender, for example, forms sediment
Powder, Lactose, sucrose, glucose, Mannitol and silicic acid；(b) binding agent, for example, cellulose derivative, starch, alginate, bright
Glue, polyvinyl pyrrolidone, sucrose and acacia gum；(c) disintegrating agent, for example, agar, Calcium Carbonate, Rhizoma Solani tuber osi or Maninot esculenta crantz.
Starch, alginic acid, cross-linked carboxymethyl cellulose sodium, composition silicate and sodium carbonate；(d) solution retardant, for example, paraffin；E () inhales
Receive accelerator, such as quaternary ammonium compound；(f) wetting agent, for example, spermol and glyceryl monostearate, magnesium stearate etc.；(g)
Adsorbent, such as Kaolin and soap clay；(h) lubricant, for example, Pulvis Talci, calcium stearate, magnesium stearate, solid poly- two
Alcohol, sodium lauryl sulfate or their mixture.
Further, described oral solid formulation is preparation commonly used in the art, such as granule, capsule, tablet or
Pill etc..
Preferably, described pharmaceutical composition is made into capsule.
Compared with prior art, present invention has an advantage that
(1) 1:1 orlistat l- proline eutectic provided by the present invention, 1:1 orlistat l- leucine eutectic
Eutectiferous fusing point is respectively 95.3 DEG C, 130.3 DEG C and 103.5 DEG C with 3:2 orlistat l- L-Valine, is all remarkably higher than commercially available
The fusing point of the type orlistat in Orlistat Capsules agent is so that crude drug is prepared and the drying program in formulation process
Can carry out at a higher temperature, shorten drying time, improve drying efficiency, reduce energy consumption for drying.
(2) Dissolution Rate Testing finds, difficult to understand with 1:1 orlistat l- proline eutectic provided by the present invention, 1:1 respectively
Li Sita l- leucine eutectic or 3:2 orlistat l- L-Valine eutectic are crude drug, according to conventional dose method institute
The three kinds of capsules preparing are above type used in commercially available Orlistat Capsules 10 minutes and later dissolution
The dissolution of orlistat, the solubility property of modified orlistat, accelerate drug effect.
Brief description
Fig. 1 is the solution proton nmr collection of illustrative plates of commercially available medicinal orlistat.
Fig. 2 is the solution proton nmr collection of illustrative plates of 1:1 orlistat l- proline eutectic.
Fig. 3 is the solution proton nmr collection of illustrative plates of 1:1 orlistat l- leucine eutectic.
Fig. 4 is the solution proton nmr collection of illustrative plates of 3:2 orlistat l- L-Valine eutectic.
Fig. 5 is the xrpd collection of illustrative plates of 1:1 orlistat l- proline eutectic.
Fig. 6 is the xrpd collection of illustrative plates of 1:1 orlistat l- leucine eutectic.
Fig. 7 is the xrpd collection of illustrative plates of 3:2 orlistat l- L-Valine eutectic.
Fig. 8 is the dsc collection of illustrative plates of 1:1 orlistat l- proline eutectic.
Fig. 9 is the dsc collection of illustrative plates of 1:1 orlistat l- leucine eutectic.
Figure 10 is the dsc collection of illustrative plates of 3:2 orlistat l- L-Valine eutectic.
Figure 11 is the tga collection of illustrative plates of 1:1 orlistat l- proline eutectic.
Figure 12 is the tga collection of illustrative plates of 1:1 orlistat l- leucine eutectic.
Figure 13 is the tga collection of illustrative plates of 3:2 orlistat l- L-Valine eutectic.
Figure 14 is the stripping curve figure of commercially available Orlistat Capsules.
Figure 15 is the stripping curve figure of 1:1 orlistat l- proline eutectic capsule.
Figure 16 is the stripping curve figure of 1:1 orlistat l- leucine eutectic capsule.
Figure 17 is the stripping curve figure of 3:2 orlistat l- L-Valine eutectic capsule.
Specific embodiment
Further describe the present invention below by way of specific embodiment, but the present invention is not limited only to following examples.
Embodiment 1 orlistat and the preparation of aminoacid eutectic
(1) preparation research of 1:1 orlistat l- proline eutectic
Take 0.496g type orlistat (0.001mol), be placed in 100ml three-neck flask, 35 DEG C of water-baths are gently mixed down
It is slowly added dropwise acetone-normal heptane 1:1 (v/v) mixed solution, until solid is completely dissolved；It is subsequently placed in after being stirred overnight at 35 DEG C
It is cooled to room temperature, be slowly added dropwise saturation acetone-normal heptane (1:1, the v/v) solution of 0.173mg/l- proline (0.0015mol)；
It is placed at 35 DEG C in agitator ripe 3 days again；Last standing 2 days under condition of ice bath, the solid that vacuum filter separates out, will analyse
The solid going out 70 DEG C in the vacuum tank at be dried 4 hours, obtain white, needle-shaped crystals type solid 0.589g, total recovery 96.4%.
(2) preparation research of 1:1 orlistat l- leucine eutectic
Take 0.496g type orlistat (0.001mol), be placed in 100ml three-neck flask, 40 DEG C of water-baths are gently mixed down
It is slowly added dropwise n-octyl alcohol, until solid is completely dissolved；It is subsequently placed in and is cooled to room temperature after being stirred overnight at 40 DEG C, be slowly added dropwise
The saturation n-octyl alcohol solution of 0.197mg/l- leucine (0.0015mol)；It is placed at 40 DEG C in agitator ripe 3 days again；?
The standing solid that after 2 days, vacuum filter separates out under condition of ice bath afterwards, the solid of precipitation is placed at 70 DEG C in vacuum tank and is dried 4
Hour, obtain white flaky crystals 0.617g, total recovery is 98.4%.
(3) preparation research of 3:2 orlistat l- L-Valine eutectic
Take 0.496g type orlistat (0.001mol), be placed in 100ml three-neck flask, 35 DEG C of water-baths are gently mixed down
It is slowly added dropwise isopropanol-chloroform (1:1) mixed solvent, until solid is completely dissolved；It is subsequently placed at 35 DEG C cold after being stirred overnight
But to room temperature, it is slowly added dropwise saturation isopropanol-chloroform (1:1) saturated solution of 0.176mg/l- L-Valine (0.0015mol)；Again
It is placed at 35 DEG C in agitator ripe 3 days；The last standing solid that after 2 days, vacuum filter separates out under condition of ice bath, will analyse
The solid going out is placed in and is dried 4 hours at 70 DEG C in vacuum drying oven, obtains canescence flaky crystal 0.547g, total recovery 54.7%.
Embodiment 2 orlistat and the mensure of aminoacid eutectic melting point
Difficult to understand according to the 1:1 that the fusing point automatic analyzer method that " Chinese Pharmacopoeia " version in 2015 is recorded is obtained respectively to embodiment 1
Li Sita l- proline eutectic, 1:1 orlistat l- leucine eutectic and 3:2 orlistat l- L-Valine eutectic carry out fusing point and
Melting range measures, and result see table 1.
Table 1 orlistat and aminoacid eutectiferous fusing point test result
| Eutectic formation (ccf) | Orlistat: ccf (molecular number ratio/mol ratio) | Eutectic melting point (DEG C) | Eutectic melting range (DEG C) |
| L- proline | 1:1 | 92.5 | <1 |
| L- leucine | 1:1 | 130.3 | <1 |
| L- L-Valine | 3:2 | 103.5 | <1 |
Result shows, 1:1 orlistat l- proline eutectic that the present invention is obtained, 1:1 orlistat l- leucine eutectic
Narrow with the melting range of 3:2 orlistat l- L-Valine eutectic (< 1 DEG C), show that prepared eutectic purity is high, be single pure
Thing.And the eutectiferous fusing point being obtained is all remarkably higher than the fusing point of the type orlistat in commercially available Orlistat Capsules agent
(43℃).
Embodiment 3 orlistat and the sign of aminoacid eutectic
Be respectively adopted nuclear magnetic resonance, NMR (1H-nmr), Powder x-ray diffraction (xrpd), differential scanning calorimetry (dsc), heat
1:1 orlistat l- proline eutectic that weight analysis (tga) are obtained respectively to embodiment 1,1:1 orlistat l- leucine eutectic
Carry out structural characterization with 3:2 orlistat l- L-Valine eutectic, thus being further characterized by the formation of eutectic, every instrument characterizing
As shown in the table with condition.
Specifically:
(1) solution proton nmr: be equipped with Autosampler the bruker-400mhz being controlled by drx400 control station
Record on wavelength spectrometer1H-nmr composes.Dissolve a sample in and be used in d6-dmso analyzing.Loaded real using the bruker of standard
Test, to obtain data using the icon-nmr v4.0.4 (construction 1) running with topsin v1.3 (Patch-level 8).
Result: the solution proton nmr collection of illustrative plates of orlistat is as shown in Figure 1；
Solution proton nmr collection of illustrative plates such as Fig. 2 institute of preparation-obtained 1:1 orlistat l- proline eutectic in embodiment 1
Show, the integral area at all peaks is 4.3 times of peak integral area in the range of 0.88～0.94ppm, thus illustrate orlistat with
L- proline system forms eutectic with the mol ratio of 1:1；
Solution proton nmr collection of illustrative plates such as Fig. 3 institute of preparation-obtained 1:1 orlistat l- leucine eutectic in embodiment 1
Show, the integral area at all peaks is 5.2 times of peak integral area in the range of 0.88～0.94ppm, thus illustrate orlistat with
L- leucine system forms eutectic with the mol ratio of 1:1；
Solution proton nmr collection of illustrative plates such as Fig. 4 institute of preparation-obtained 3:2 orlistat l- L-Valine eutectic in embodiment 1
Show, the integral area at all peaks is 4.9 times of peak integral area in the range of 0.88～0.94ppm, thus illustrate orlistat with
L- L-Valine system forms eutectic with the mol ratio of 3:2.
(2) x- ray powder diffraction (xrpd) characterizes: is received using cuk α radiation (40kv, 40ma), θ -2 θ clinometer, v4
Slit, ge monochromator and lynxeye detector, obtain the x- ray powder diffraction pattern of sample on bruker d8 diffractometer.
Using certified corundum standard (nist1976), performance checking is carried out to instrument, using the step-length of 0.05 ° of 2 θ and 0.5 second
Stepping time, in 0 ° to 50 ° of 2 θ of angular range internal environment temperature collection data.Using the not ground powder receiving
End, the sample preparation run at ambient conditions is flat board sample.About 35mg sample is gently stacked into be cut into polished,
Intracavity in the silicon chip of zero background (510).Using diffrac plus eva v11.0.02 or v13.0.0.2, to all samples
It is analyzed.
Result: in embodiment 1, the xrpd figure of preparation-obtained 1:1 orlistat l- proline eutectic is shown in Fig. 5, and it is main
Absworption peak is as shown in table 2 below.
The xrpd measurement result of table 2 1:1 orlistat l- proline eutectic
In embodiment 1, the xrpd figure of preparation-obtained 1:1 orlistat l- leucine eutectic is shown in Fig. 6, and it mainly absorbs
Peak is as shown in table 3 below.
The xrpd measurement result of table 3 1:1 orlistat l- leucine eutectic
| Angle (° 2 θ ± 0.2 ° 2 θ) | D value (angstrom) | Intensity (%) |
| 9.4 | 9.5 | m |
| 11.2 | 7.9 | vw |
| 12.2 | 7.3 | w |
| 12.4 | 7.0 | w |
| 13.4 | 6.7 | vw |
| 16.5 | 5.32 | w |
| 16.9 | 5.23 | w |
| 17.6 | 5.04 | w |
| 18.5 | 4.73 | s |
| 19.3 | 4.60 | m |
| 20.8 | 4.26 | w |
| 22.4 | 3.97 | m |
| 24.9 | 3.57 | vs |
| 26.6 | 3.38 | m |
| 27.0 | 3.31 | vs |
| 27.6 | 3.20 | m |
| 28.4 | 3.16 | m |
| 28.6 | 3.10 | m |
| 34.6 | 2.58 | w |
| 36.2 | 2.49 | m |
In embodiment 1, the xrpd figure of preparation-obtained 3:2 orlistat l- L-Valine eutectic is shown in Fig. 7, and it mainly absorbs
Peak is as shown in table 4 below.
The xrpd measurement result of table 4 3:2 orlistat l- L-Valine eutectic
| Angle (° 2 θ ± 0.2 ° 2 θ) | D value (angstrom) | Intensity (%) |
| 9.2 | 9.2 | vw |
| 11.2 | 7.9 | w |
| 12.0 | 7.2 | m |
| 12.6 | 7.0 | vw |
| 13.3 | 6.6 | m |
| 14.8 | 5.98 | vw |
| 15.7 | 5.63 | vw |
| 16.8 | 5.28 | m |
| 17.0 | 5.20 | m |
| 17.6 | 5.03 | m |
| 18.4 | 4.82 | vw |
| 19.0 | 4.67 | s |
| 19.3 | 4.60 | vs |
| 19.6 | 4.54 | m |
| 20.9 | 4.24 | w |
| 21.5 | 4.14 | w |
| 22.2 | 4.00 | shoulder |
| 22.4 | 3.96 | s |
| 23.6 | 3.74 | m |
| 24.3 | 3.64 | m |
| 24.9 | 3.56 | vs |
| 26.2 | 3.37 | m |
| 27.1 | 3.30 | s |
| 27.8 | 3.20 | vs |
| 28.7 | 3.11 | m |
| 34.6 | 2.49 | w |
(3) heat analysis-means of differential scanning calorimetry (dsc): on the ta instrument q2000 being equipped with 50 position Autosamplers
Collect dsc data.Carry out the calibration of thermal capacity using sapphire, and carry out the calibration of energy and temperature using certified indium.
Under normal circumstances, in pin hole aluminium dish, 10 DEG C/min of each samples by 0.8～1.2mg are from 25 DEG C of receipts to 350 DEG C.In sample
The dry nitrogen air-flow of projecting 50ml/ minute on product.Instrument control software be advantage (for q series, v2.8.0.392) and
thermal advantage v4.8.3.Carry out all data analysiss using universal analysis v4.3a software.
Result: the 1:1 orlistat l- proline eutectic preparing in embodiment 1,1:1 orlistat l- leucine are common
The brilliant dsc figure with 3:2 orlistat l- L-Valine eutectic is shown in Fig. 8, Fig. 9 and Figure 10 respectively.
(3) thermogravimetric analysiss (tga): tga number is collected on the ta instrument q500tga be equipped with 16 position Autosamplers
According to.Using certified alumel (alumel), temperature correction is carried out to described instrument.Under normal circumstances, by 5～30mg's
Each sample is loaded on the aluminum dsc disk of the platinum crucible eliminating tare weight in advance, and is heated from room temperature with 10 DEG C/min of speed
To 350 DEG C.The nitrogen of 60ml/ minute is kept on sample.Instrument control software be advantage (for q series,
) and thermal advantage v4.8.3 v2.8.0.392.
Result: the 1:1 orlistat l- proline eutectic preparing in embodiment 1,1:1 orlistat l- leucine are common
The brilliant tga figure with 3:2 orlistat l- L-Valine eutectic is shown in Figure 11, Figure 12 and Figure 13 respectively.
Embodiment 4 contains the preparation of orlistat and aminoacid eutectic capsule
(1) prescription composition
Described eutectic is 1:1 orlistat l- proline eutectic, 1:1 orlistat l- leucine eutectic or 3:2 profit difficult to understand
Take charge of his l- L-Valine eutectic.
(2) capsule preparation
1. mix: in advance sodium lauryl sulphate, Crospovidone, carboxymethylstach sodium, Microcrystalline Cellulose are crossed 80 mesh sieves,
Obtain fine powder standby；Then sodium lauryl sulphate, Crospovidone, carboxymethylstach sodium and Microcrystalline Cellulose are weighed by recipe quantity thin
Powder and eutectic；First by sodium lauryl sulphate, Crospovidone, carboxymethylstach sodium mix homogeneously, add Microcrystalline Cellulose
With eutectic mix homogeneously, cross twice of 80 mesh sieve, obtain final product the powder of mixing.
2. pelletize and be dried: be slowly added to 50% ethanol solution containing 10% polyvidone k30 toward in the powder mixing, system is soft
Material, 20 mesh extruded sieve series wet granular, and wet granular is put in 60 DEG C of air dry ovens and dried 6 hours, takes out 20 mesh sieve granulate.
3. particle content measuring: carry out by content assaying method in quality standard, measure orlistat in dry particle and contain
Amount, calculates theoretical loading amount.
4. fill capsule: by the theoretical loading amount calculating, dry particle is filled into No. 0 capsule (mainly by gelatin, titanium white
Powder, lemon yellow, light blue are constituted) in.
Embodiment 5 contains the dissolution determination of orlistat and aminoacid eutectic capsule
Measure commercially available Orlistat Capsules (middle mountain ten thousand Chinese medical sci-tech according to 2015 editions two annex xc slurry processes of Chinese Pharmacopoeia
Company limited provide, lot number 0015856) with implement 4 in prepare the capsule containing various eutectics dissolution (with
3.5% lauryl sodium sulfate aqueous solution is dissolution medium).Average dissolution such as table 5 below institute under each time point of various capsule
Show.The 1:1 orlistat l- proline capsule for preparing in commercially available Orlistat Capsules, embodiment 4,1:1 orlistat l-
The stripping curve of leucine capsule and 3:2 orlistat l- L-Valine capsule is shown in Figure 14, Figure 15, Figure 16 and Figure 17 respectively.
Table 5 contains the dissolution determination of orlistat and aminoacid eutectic capsule
The above is only the preferred embodiment of the present invention it is noted that above-mentioned preferred implementation be not construed as right
The restriction of the present invention, protection scope of the present invention should be defined by claim limited range.For the art
For those of ordinary skill, without departing from the spirit and scope of the present invention, some improvements and modifications can also be made, these change
Enter and retouch also to should be regarded as protection scope of the present invention.
Claims (10)
1. a kind of orlistat with aminoacid eutectic it is characterised in that described aminoacid is selected from: the bright ammonia of l- proline, l-
One of acid or l- L-Valine.
2. eutectic according to claim 1 is it is characterised in that described orlistat and l- proline rubbing with 1:1
You form eutectic by ratio.
3. eutectic according to claim 2 is it is characterised in that described orlistat and the eutectiferous x- of l- proline
Ray powder diffraction pattern has characteristic absorption peak at 19.2 °, 22.6 °, 25.0 ° and 27.1 ° of 2 θ ± 0.2 ° 2 θ angle.
4. eutectic according to claim 1 is it is characterised in that described orlistat and l- leucine rubbing with 1:1
You form eutectic by ratio.
5. eutectic according to claim 4 is it is characterised in that described orlistat and the eutectiferous x- of l- leucine
Ray powder diffraction pattern has characteristic absorption peak at 9.4 °, 18.5 °, 19.3 °, 24.9 ° and 27.0 ° of 2 θ ± 0.2 ° 2 θ angle.
6. eutectic according to claim 1 is it is characterised in that described orlistat and l- L-Valine rubbing with 3:2
You form eutectic by ratio.
7. eutectic according to claim 6 is it is characterised in that described orlistat and the eutectiferous x- of l- L-Valine
Ray powder diffraction pattern has characteristic absorption at 19.0 °, 19.3 °, 22.4 °, 24.9 °, 27.1 ° and 27.8 ° of 2 θ ± 0.2 ° 2 θ angle
Peak.
8. a kind of pharmaceutical composition it is characterised in that described pharmaceutical composition comprise as arbitrary in claim 1-7 described extremely
A kind of few eutectic.
9. pharmaceutical composition according to claim 8 is it is characterised in that described pharmaceutical composition is oral administration solid system
Agent, described oral solid formulation, using the arbitrary described at least one eutectic of claim 1-7 as effective ingredient, is equipped with medicine
Learn acceptable additive to be prepared from.
10. pharmaceutical composition according to claim 9 is it is characterised in that described oral solid formulation is capsule.
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| WO2021097650A1 (en) * | 2019-11-19 | 2021-05-27 | 中山万汉制药有限公司 | Cocrystal of orlistat and amino acid, and pharmaceutical composition comprising same |
| CN112998133A (en) * | 2021-02-24 | 2021-06-22 | 中国科学院上海药物研究所 | Plant essential oil amino acid composition and preparation method thereof |
| CN112998133B (en) * | 2021-02-24 | 2022-08-23 | 中国科学院上海药物研究所 | Plant essential oil amino acid composition and preparation method thereof |
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