The eutectic of orlistat and amino acid and include eutectiferous pharmaceutical composition
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to the eutectic of orlistat and amino acid and include the eutectic
Pharmaceutical composition.
Background technology
Orlistat (orlistat) is to research and develop lipase inhibitor class slimming drugs, trade name by company of Roche Group
Xenical, the last century nineties end take the lead in listing in America and Europe, are eaten in Discussion on Chinese Listed, and in 2005 by China within 2001
The approval of product Drug Administration switchs to non-prescribed medicine.Its entitled N- formyls-L-Leu (s) -1 of chemistry [(2s, 3s) 3- oneself
- 4 oxygroup -2- glycidyl methyl of base] ten diester, also referred to as tetrahydrolipostatin (Tetrahydrolipstatin, THL) they are a kind of
Semi-synthetic lipstatin derivative, chemical structural formula are as shown below:
With the capsule of its II crystal form and tablet hyoscine and at present, unique one kind does not influence to eat orlistat both at home and abroad
Desire, the chemical slimming drugs for not acting on central nervous system, security features are superior.II 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 ethyl alcohol, and in life to be white
It manages in pH value range without pKa value.At present, there are two types of methods for domestic production orlistat:One kind is chemical fully synthetic, reaction step
More, yield is low, and environment compatibility is poor;Another kind is that microbial fermentation obtains orlistat intermediate, and then intermediate is through a step
Hydrogenation synthesis orlistat, the orlistat of second method production are occupied an leading position.No matter which kind of method, be required for last
The orlistat of one step chemical reaction gained is dried, to remove moisture and organic solvent in product.And II crystal form Ao Lisi
His fusing point is only 43 DEG C, so as to need to giving temperature and time stringent control in bulk pharmaceutical chemicals and finished dosage form drying process
System.
The low melting point and dissolubility difference of orlistat directly limit its application, and fusing point and dissolubility often with substance
Crystal form is related.The research about orlistat crystal form has in the prior art:International monopoly WO2005026140 discloses I type and II
The characteristic parameter collection of illustrative plates of the preparation method of type orlistat and two kinds of crystal forms, such as X-ray diffraction (XRD) collection of illustrative plates, differential scanning
Calorimetric (DSC) collection of illustrative plates and infrared analysis (IR) collection of illustrative plates.Separately have, international monopoly WO2010084502 discloses a kind of orlistat knot
Crystalline form and its XRD and IR characteristic parameters, which is in polar solvent and non-polar organic solvent by solid orlistat
It recrystallizes and obtains in mixed system, the preferred acetone-heptane system of the solvent mixed system, but not publicly mixed in the patent
Various solvent proportions in zoarium system, also whether the other structures feature of undisclosed gained orlistat crystal form (is molten
Object is closed in agent) and pharmacological activity parameter.In addition, international monopoly WO2003047531 also discloses I type and II type of orlistat
The XRD spectrum of crystal form and both crystal forms, thermogravimetric analysis (TGA) collection of illustrative plates and DSC collection of illustrative plates, the preparation side of crystallization
Method and the solid pharmaceutical preparation containing this two kinds of crystal forms, but undisclosed reactive dyes, do not disclose this two kinds of crystal forms and the world
I type of orlistat disclosed in patent WO2005026140 and II type compare have what advantage.
Eutectic refers to that active constituents of medicine (Active pharmaceutical ingredient, API) and eutectic are formed
The crystal that object (cocrystal former, CCF) is combined under the action of hydrogen bond or other non-covalent bonds, wherein API with
CCF is solid at room temperature in pure state, and there are fixed stoichiometric ratios between each component.It, can be with after API forms eutectic
Fusing point, to draw moist, stability, solubility and dissolution rate, bioavilability, bioavilability, release, mechanical performance etc. many
Aspect can make moderate progress, therefore eutectic theory has broad application prospects in new drug research field.
Eutectic formation is prepared currently without about using orlistat and amino acid, there are fusing points to overcome orlistat
Low, the defects of dissolubility is poor relevant report.
Invention content
To solve technical problem in the prior art, the purpose of the present invention is to provide a kind of orlistat and amino
Acid eutectic and include eutectiferous pharmaceutical composition.The eutectic has higher fusing point, can reduce bulk pharmaceutical chemicals
With, to the requirement of drying condition, and with higher dissolution rate, accelerating drug effect in the preparation process of preparation.
The present invention is by following technical solution to realize above-mentioned purpose:
On the one hand, for the present invention using fusing point and melting range as index, having investigated will be a variety of normal using conventional eutectic preparation method
The amino acid seen and orlistat are prepared into eutectiferous possibility, the eutectic preparation method be medicinal chemistry art institute
The method known, such as the preparation method (chemistry about pharmaceutical co-crystals that Gao Yuan et al. is disclosed in " pharmaceutical co-crystals progress "
Progress, 2010,05:829-836), it is incorporated herein by reference.It is as a result, it has been found that potential common in the amino acids for receiving to investigate
In brilliant formation, only L-Leu, Valine, L-PROLINE can be in different solvents using cooling crystallization method and Ao Lisi
He formed melting range it is narrow (<1 DEG C) crystalline material, illustrate to form single pure substance.
On the other hand, the present invention be respectively adopted nuclear magnetic resonance (1H-NMR), powder x-ray diffraction (XRPD), differential scanning
The eutectic that calorimetry (DSC), thermogravimetric analysis (TGA) form orlistat and above-mentioned eutectic formation has carried out structure table
Sign, so as to further demonstrate the formation of eutectic.
Based on this, the present invention provides a kind of orlistat and amino acid eutectic, and the amino acid is selected from:L- dried meat ammonia
One kind in acid, L-Leu or Valine.
Further, the orlistat and L-PROLINE are with 1:1 molar ratio forms eutectic.
Further, the orlistat and L-Leu are with 1:1 molar ratio forms eutectic.
Further, the orlistat and Valine are with 3:2 molar ratio forms eutectic.
Further, the orlistat and the eutectiferous X-ray powder diffraction figure of L-PROLINE 19.2 °,
22.6 °, 25.0 ° with 27.1 ° of 2 θ ± 0.2 °, 2 θ angles at have characteristic absorption peak.
Further, the orlistat and the eutectiferous X-ray powder diffraction figure of L-Leu 9.4 °,
18.5 °, 19.3 °, 24.9 ° with 27.0 ° of 2 θ ± 0.2 °, 2 θ angles at have characteristic absorption peak.
Further, the orlistat and the eutectiferous X-ray powder diffraction figure of Valine 19.0 °,
19.3 °, 22.4 °, 24.9 °, 27.1 ° with 27.8 ° of 2 θ ± 0.2 °, 2 θ angles at have characteristic absorption peak.
Moreover, it relates to a kind of containing eutectiferous pharmaceutical composition, which is oral solid
Body preparation, with orlistat L-PROLINE eutectic, orlistat L-Leu eutectic, orlistat Valine eutectic
At least one of as active ingredient, be equipped with pharmaceutically acceptable additive and be prepared.The additive does not change substantially
Become orlistat and amino acids formed eutectic, will not occur any effect with any ingredient in pharmaceutical composition and with
Orlistat amino acid eutectic used is incompatible.
The oral solid formulation is prepared by method known in field of pharmaceutical preparations, for example, with reference to Cui Fude
Chief editor,《Pharmacy》(the 7th edition) (People's Health Publisher's publication).It specifically, can be by 1:1 orlistat L-PROLINE is total to
Crystalline substance, 1:1 orlistat L-Leu eutectic or 3:2 orlistat Valine eutectics and at least one pharmaceutically acceptable tax
Shape agent mixes, and the excipient can be citric acid or Dicalcium Phosphate or be (a) filler or incremental agent, for example, forming sediment
Powder, lactose, sucrose, glucose, mannitol and silicic acid;(b) adhesive, for example, cellulose derivative, starch, alginate, bright
Glue, polyvinylpyrrolidone, sucrose and acacia gum;(c) disintegrant, for example, agar, calcium carbonate, potato or cassava
Starch, alginic acid, cross-linked carboxymethyl cellulose sodium, composition silicate and sodium carbonate;(d) solution retardant, for example, paraffin;(e) it inhales
Receive accelerating agent, such as quaternary ammonium compound;(f) wetting agent, for example, cetanol and glycerin monostearate, magnesium stearate etc.;(g)
Adsorbent, such as kaolin and soap clay;(h) lubricant, for example, talcum powder, calcium stearate, magnesium stearate, solid poly- two
Alcohol, NaLS or their mixture.
Further, the oral solid formulation be preparation commonly used in the art, as granule, capsule, tablet or
Pill etc..
Preferably, the pharmaceutical composition is made into capsule.
Compared with prior art, advantage of the invention is that:
(1) provided by the present invention 1:1 orlistat L-PROLINE eutectic, 1:1 orlistat L-Leu eutectic
With 3:The 2 eutectiferous fusing points of orlistat Valine are respectively 95.3 DEG C, 130.3 DEG C and 103.5 DEG C, are all remarkably higher than commercially available
The fusing point of II type orlistat in orlistat capsule so that bulk pharmaceutical chemicals are prepared and the drying program in formulation process
It can carry out at a higher temperature, shorten drying time, improve drying efficiency, reduce energy consumption for drying.
(2) Dissolution Rate Testing is found, respectively with provided by the present invention 1:1 orlistat L-PROLINE eutectic, 1:1 is difficult to understand
Li Sita L-Leus eutectic or 3:2 orlistat Valine eutectics are bulk pharmaceutical chemicals, according to conventional dose method institute
Three kinds of capsules being prepared were above II type used in commercially available orlistat capsule 10 minutes and later dissolution rate
The dissolution rate of orlistat, the solubility property of modified orlistat, accelerates drug effect.
Description of the drawings
Fig. 1 is the solution proton NMR spectra of commercially available medicinal II type orlistat.
Fig. 2 is 1:The solution proton NMR spectra of 1 orlistat L-PROLINE eutectic.
Fig. 3 is 1:The solution proton NMR spectra of 1 orlistat L-Leu eutectic.
Fig. 4 is 3:The solution proton NMR spectra of 2 orlistat Valine eutectics.
Fig. 5 is 1:The XRPD collection of illustrative plates of 1 orlistat L-PROLINE eutectic.
Fig. 6 is 1:The XRPD collection of illustrative plates of 1 orlistat L-Leu eutectic.
Fig. 7 is 3:The XRPD collection of illustrative plates of 2 orlistat Valine eutectics.
Fig. 8 is 1:The DSC collection of illustrative plates of 1 orlistat L-PROLINE eutectic.
Fig. 9 is 1:The DSC collection of illustrative plates of 1 orlistat L-Leu eutectic.
Figure 10 is 3:The DSC collection of illustrative plates of 2 orlistat Valine eutectics.
Figure 11 is 1:The TGA collection of illustrative plates of 1 orlistat L-PROLINE eutectic.
Figure 12 is 1:The TGA collection of illustrative plates of 1 orlistat L-Leu eutectic.
Figure 13 is 3:The TGA collection of illustrative plates of 2 orlistat Valine eutectics.
Figure 14 is the dissolution curve of commercially available orlistat capsule.
Figure 15 is 1:The dissolution curve of 1 orlistat L-PROLINE eutectic capsule.
Figure 16 is 1:The dissolution curve of 1 orlistat L-Leu eutectic capsule.
Figure 17 is 3:The dissolution curve of 2 orlistat Valine eutectic capsules.
Specific embodiment
The present invention is further described, but the present invention is not limited only to following embodiment below by way of specific embodiment.
The preparation of 1 orlistat of embodiment and amino acid eutectic
(1)1:The preparation research of 1 orlistat L-PROLINE eutectic
II type orlistats (0.001mol) of 0.496g are taken, are placed in 100mL three-neck flasks, 35 DEG C of water-baths are gently mixed down
Acetone-normal heptane 1 is slowly added dropwise: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, saturation acetone-normal heptane (1 of 0.173mg/L- proline (0.0015mol) is slowly added dropwise:1, v/v) solution;
It is placed in again at 35 DEG C in oscillator 3 days ripe;2 days finally are stood under condition of ice bath, the solid that vacuum filter is precipitated will analyse
The solid gone out is 4 hours dry at 70 DEG C in vacuum tank, obtains white, needle-shaped crystals type solid 0.589g, total recovery 96.4%.
(2)1:The preparation research of 1 orlistat L-Leu eutectic
II type orlistats (0.001mol) of 0.496g are taken, are placed in 100mL three-neck flasks, 40 DEG C of water-baths are gently mixed down
N-octyl alcohol is slowly added dropwise, until solid is completely dissolved;It is subsequently placed at 40 DEG C and is stirred overnight postcooling to room temperature, be slowly added dropwise
The saturation n-octyl alcohol solution of 0.197mg/L- leucines (0.0015mol);It is placed in again at 40 DEG C in oscillator 3 days ripe;Most
The solid of precipitation is placed in vacuum tank at 70 DEG C dry 4 by the solid that vacuum filter is precipitated after being stood 2 days under condition of ice bath afterwards
Hour, obtain white flaky crystals 0.617g, total recovery 98.4%.
(3)3:The preparation research of 2 orlistat Valine eutectics
II type orlistats (0.001mol) of 0.496g are taken, are placed in 100mL three-neck flasks, 35 DEG C of water-baths are gently mixed down
Isopropanol-chloroform (1 is slowly added dropwise:1) mixed solvent, until solid is completely dissolved;Be subsequently placed at 35 DEG C be stirred overnight it is rear cold
But to room temperature, saturation isopropanol-chloroform (1 of 0.176mg/L- valines (0.0015mol) is slowly added dropwise:1) saturated solution;Again
It is placed at 35 DEG C in oscillator 3 days ripe;The solid that vacuum filter is precipitated after finally being stood 2 days under condition of ice bath, will analyse
The solid gone out is placed in vacuum drying chamber drying 4 hours at 70 DEG C, obtains canescence flaky crystal 0.547g, total recovery 54.7%.
The measure of 2 orlistat of embodiment and amino acid eutectic melting point
According to《Chinese Pharmacopoeia》The fusing point automatic analyzer method that version in 2015 is recorded is to 1 made from the difference of embodiment 1:1 is difficult to understand
Li Sita L-PROLINEs eutectic, 1:1 orlistat L-Leu eutectic and 3:2 orlistat Valine eutectics carry out fusing point and
Melting range measures, and as a result see the table below 1.
1 orlistat of table and the eutectiferous fusing point test result of amino acid
Eutectic formation (CCF) |
Orlistat:CCF (molecular number ratio/molar ratio) |
Eutectic melting point (DEG C) |
Eutectic melting range (DEG C) |
L-PROLINE |
1:1 |
92.5 |
<1 |
L-Leu |
1:1 |
130.3 |
<1 |
Valine |
3:2 |
103.5 |
<1 |
The results show that produced by the present invention 1:1 orlistat L-PROLINE eutectic, 1:1 orlistat L-Leu eutectic
With 3:The melting ranges of 2 orlistat Valine eutectics it is narrow (<1 DEG C), show that eutectic purity obtained is high, be single pure
Object.And eutectiferous fusing point obtained is all remarkably higher than the fusing point of II type orlistat in commercially available orlistat capsule
(43℃)。
The characterization of 3 orlistat of embodiment and amino acid eutectic
Be respectively adopted nuclear magnetic resonance (1H-NMR), powder x-ray diffraction (XRPD), differential scanning calorimetry (DSC), heat
Weight analysis (TGA) is to 1 made from the difference of embodiment 1:1 orlistat L-PROLINE eutectic, 1:1 orlistat L-Leu eutectic
With 3:2 orlistat Valine eutectics carry out structural characterization, so as to further confirm the formation of eutectic, the instrument of items characterization
It is as shown in the table with condition.
Specifically:
(1) solution proton NMR:In the Bruker-400MHz controlled equipped with Autosampler and by DRX400 consoles
It is recorded on wavelength spectrometer1H-NMR is composed.It dissolves a sample in d6-DMSO and is used to analyze.It is loaded using the Bruker of standard real
It tests, the ICON-NMR v4.0.4 run with Topsin v1.3 (Patch-level 8) (construction 1) is utilized to obtain data.
As a result:The solution proton NMR spectra of orlistat is as shown in Figure 1;
Preparation-obtained 1 in embodiment 1:Solution proton NMR spectra such as Fig. 2 institutes of 1 orlistat L-PROLINE eutectic
Show, the integral area at all peaks is 4.3 times of peak integral area in the range of 0.88~0.94ppm, so as to illustrate orlistat with
L-PROLINE system is with 1:1 molar ratio forms eutectic;
Preparation-obtained 1 in embodiment 1:Solution proton NMR spectra such as Fig. 3 institutes of 1 orlistat L-Leu eutectic
Show, the integral area at all peaks is 5.2 times of peak integral area in the range of 0.88~0.94ppm, so as to illustrate orlistat with
L-Leu system is with 1:1 molar ratio forms eutectic;
Preparation-obtained 3 in embodiment 1:Solution proton NMR spectra such as Fig. 4 institutes of 2 orlistat Valine eutectics
Show, the integral area at all peaks is 4.9 times of peak integral area in the range of 0.88~0.94ppm, so as to illustrate orlistat with
Valine system is with 3:2 molar ratio forms eutectic.
(2) X-ray powder diffraction (XRPD) characterizes:It is received using CuK α radiation (40kV, 40mA), θ -2 θ angular instruments, V4
Slit, Ge monochromators and Lynxeye detectors obtain the X-ray powder diffraction figure sample of sample on Bruker D8 diffractometers.
Performance checking is carried out to instrument using certified Corundum standards (NIST1976), uses the step-length of 0.05 ° of 2 θ and 0.5 second
Stepping time, in the angular range internal environment temperature collection data of 0 ° to 50 ° 2 θ.Use the not ground powder of reception
The sample preparation run at ambient conditions is flat board sample by end.About 35mg samples are gently stacked into be cut into it is polished,
Intracavitary 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.
As a result:Preparation-obtained 1 in embodiment 1:The XRPD figures of 1 orlistat L-PROLINE eutectic are shown in Fig. 5, main
Absorption peak is as shown in table 2 below.
Table 21:The XRPD measurement results of 1 orlistat L-PROLINE eutectic
Preparation-obtained 1 in embodiment 1:The XRPD figures of 1 orlistat L-Leu eutectic are shown in Fig. 6, mainly absorb
Peak is as shown in table 3 below.
Table 31:The XRPD measurement results of 1 orlistat L-Leu eutectic
Angle (° 2 θ ± 0.2 °, 2 θ) |
D values (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 |
Preparation-obtained 3 in embodiment 1:The XRPD figures of 2 orlistat Valine eutectics are shown in Fig. 7, mainly absorb
Peak is as shown in table 4 below.
Table 43:The XRPD measurement results of 2 orlistat Valine eutectics
Angle (° 2 θ ± 0.2 °, 2 θ) |
D values (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-differential scanning calorimetry (DSC):On the TA instruments Q2000 equipped with 50 position Autosamplers
Collect DSC data.The calibration of thermal capacity is carried out using sapphire, and the calibration of energy and temperature is carried out using certified indium.
Under normal conditions, 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 50mL/ minutes is hung upside down on product.Instrument control software be Advantage (for Q series, v2.8.0.392) and
Thermal Advantage v4.8.3.All data analyses are carried out using Universal Analysis v4.3A softwares.
As a result:1 be prepared in embodiment 1:1 orlistat L-PROLINE eutectic, 1:1 orlistat L-Leu is total to
Crystalline substance and 3:The DSC figures of 2 orlistat Valine eutectics are shown in Fig. 8, Fig. 9 and Figure 10 respectively.
(3) thermogravimetric analysis (TGA):TGA numbers are collected on the TA instruments Q500TGA equipped with 16 position Autosamplers
According to.Temperature correction is carried out to the instrument using certified alumel (Alumel).Under normal conditions, by 5~30mg's
Each sample is loaded on the aluminium DSC disks of platinum crucible for eliminating tare weight in advance, and is heated with 10 DEG C/min of speed from room temperature
To 350 DEG C.The nitrogen of 60mL/ minutes is kept on sample.Instrument control software be Advantage (for Q series,
) and Thermal Advantage v4.8.3 v2.8.0.392.
As a result:1 be prepared in embodiment 1:1 orlistat L-PROLINE eutectic, 1:1 orlistat L-Leu is total to
Crystalline substance and 3:The TGA figures of 2 orlistat Valine eutectics are shown in Figure 11, Figure 12 and Figure 13 respectively.
Preparation of the embodiment 4 containing orlistat Yu amino acid eutectic capsule
(1) composition
The eutectic is 1:1 orlistat L-PROLINE eutectic, 1:1 orlistat L-Leu eutectic or 3:2 profits difficult to understand
Take charge of his Valine eutectic.
(2) prepared by capsule
1. it mixes:Lauryl sodium sulfate, crospovidone, carboxyrnethyl starch sodium, microcrystalline cellulose are crossed into 80 mesh sieve in advance,
It is spare to obtain fine powder;Then it is thin lauryl sodium sulfate, crospovidone, carboxyrnethyl starch sodium and microcrystalline cellulose to be weighed by recipe quantity
Powder and eutectic;First lauryl sodium sulfate, crospovidone, carboxyrnethyl starch sodium are uniformly mixed, add microcrystalline cellulose
It is uniformly mixed with eutectic, crosses 80 mesh and sieve twice of powder to get mixing.
2. granulation and drying:50% ethanol solution containing 10% PVP K30 is slowly added into the powder of mixing, system is soft
Material, 20 mesh squeezed sieve series wet granular, and wet granular, which is put in 60 DEG C of air dry ovens, dries 6 hours, took out 20 mesh sieve whole grain.
3. particle content measuring:It is carried out by content assaying method in quality standard, measures orlistat in dry particle and contain
Amount calculates theoretical loading amount.
4. filling capsule:By the theoretical loading amount calculated, dry particle is filled into No. 0 capsule (mainly by gelatin, titanium white
Powder, lemon yellow, brilliant blue are formed) in.
Dissolution determination of the embodiment 5 containing orlistat Yu amino acid eutectic capsule
Commercially available orlistat capsule (middle ten thousand Chinese medical sci-tech of mountain is measured according to 2015 editions two annex XC slurry processes of Chinese Pharmacopoeia
Co., Ltd provide, lot number 0015856) with implement 4 in be prepared the capsule containing various eutectics dissolution rate (with
3.5% lauryl sodium sulfate aqueous solution is dissolution medium).Average dissolution rate such as the following table 5 institute under various capsule each time points
Show.1 be prepared in commercially available orlistat capsule, embodiment 4:1 orlistat L-PROLINE capsule, 1:1 orlistat L-
Leucine capsule and 3:The stripping curve of 2 orlistat Valine capsules is shown in Figure 14, Figure 15, Figure 16 and Figure 17 respectively.
Dissolution determination of the table 5 containing orlistat Yu amino acid eutectic capsule
It the above is only the preferred embodiment of the present invention, it is noted that above-mentioned preferred embodiment is not construed as pair
The limitation of the present invention, protection scope of the present invention should be subject to claim limited range.For the art
For those of ordinary skill, without departing from the spirit and scope of the present invention, several improvements and modifications can also be made, these change
Protection scope of the present invention is also should be regarded as into retouching.