CN1679533A - Levo carnitine dropping pill and preparation thereof - Google Patents
Levo carnitine dropping pill and preparation thereof Download PDFInfo
- Publication number
- CN1679533A CN1679533A CN 200510008903 CN200510008903A CN1679533A CN 1679533 A CN1679533 A CN 1679533A CN 200510008903 CN200510008903 CN 200510008903 CN 200510008903 A CN200510008903 A CN 200510008903A CN 1679533 A CN1679533 A CN 1679533A
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- Prior art keywords
- carnitine
- polyethylene glycol
- mixed
- esters
- substrate
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- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 title claims abstract description 238
- 239000006187 pill Substances 0.000 title claims abstract description 82
- 229960001518 levocarnitine Drugs 0.000 title claims abstract description 72
- 238000002360 preparation method Methods 0.000 title claims description 55
- 239000000758 substrate Substances 0.000 claims abstract description 94
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 71
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 71
- 208000008589 Obesity Diseases 0.000 claims abstract description 15
- 208000019423 liver disease Diseases 0.000 claims abstract description 8
- 239000002202 Polyethylene glycol Substances 0.000 claims description 239
- 229920001223 polyethylene glycol Polymers 0.000 claims description 239
- -1 3-carboxyl-2-hydroxypropyl Chemical group 0.000 claims description 104
- 229920002472 Starch Polymers 0.000 claims description 92
- 235000019698 starch Nutrition 0.000 claims description 92
- 239000008107 starch Substances 0.000 claims description 92
- 150000002148 esters Chemical class 0.000 claims description 86
- 229920000858 Cyclodextrin Polymers 0.000 claims description 83
- 239000001116 FEMA 4028 Substances 0.000 claims description 83
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 83
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 83
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 83
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 83
- 229960004853 betadex Drugs 0.000 claims description 83
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 83
- 229920001983 poloxamer Polymers 0.000 claims description 83
- 229960000502 poloxamer Drugs 0.000 claims description 83
- 239000011734 sodium Substances 0.000 claims description 83
- 229910052708 sodium Inorganic materials 0.000 claims description 83
- 229960004203 carnitine Drugs 0.000 claims description 79
- 239000000126 substance Substances 0.000 claims description 71
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 48
- 239000001828 Gelatine Substances 0.000 claims description 24
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 24
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 24
- 235000021355 Stearic acid Nutrition 0.000 claims description 24
- 229920000159 gelatin Polymers 0.000 claims description 24
- 235000019322 gelatine Nutrition 0.000 claims description 24
- 235000011187 glycerol Nutrition 0.000 claims description 24
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 24
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 24
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 24
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 claims description 24
- 239000008117 stearic acid Substances 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 15
- 235000015424 sodium Nutrition 0.000 claims description 15
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 14
- 235000020824 obesity Nutrition 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- YNTQKXBRXYIAHM-UHFFFAOYSA-N azanium;butanoate Chemical compound [NH4+].CCCC([O-])=O YNTQKXBRXYIAHM-UHFFFAOYSA-N 0.000 claims description 5
- 239000001729 Ammonium fumarate Substances 0.000 claims description 4
- RHCDOQHJPUVQLK-PLNGDYQASA-N C[N+](C)(C)/C(\C(O)=O)=C\C([O-])=O Chemical compound C[N+](C)(C)/C(\C(O)=O)=C\C([O-])=O RHCDOQHJPUVQLK-PLNGDYQASA-N 0.000 claims description 4
- 235000019297 ammonium fumarate Nutrition 0.000 claims description 4
- CKKXWJDFFQPBQL-SEPHDYHBSA-N azane;(e)-but-2-enedioic acid Chemical compound N.N.OC(=O)\C=C\C(O)=O CKKXWJDFFQPBQL-SEPHDYHBSA-N 0.000 claims description 4
- 239000000839 emulsion Substances 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
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- 229940057995 liquid paraffin Drugs 0.000 claims description 2
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- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 2
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- 238000005303 weighing Methods 0.000 claims description 2
- 238000007493 shaping process Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 34
- 231100000331 toxic Toxicity 0.000 abstract description 2
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 abstract 1
- 230000002939 deleterious effect Effects 0.000 abstract 1
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- 238000002474 experimental method Methods 0.000 description 63
- 238000012360 testing method Methods 0.000 description 42
- 238000000034 method Methods 0.000 description 41
- 239000004615 ingredient Substances 0.000 description 37
- 239000008194 pharmaceutical composition Substances 0.000 description 36
- 239000000969 carrier Substances 0.000 description 27
- 239000004353 Polyethylene glycol 8000 Substances 0.000 description 18
- 230000000694 effects Effects 0.000 description 14
- 229940079593 drug Drugs 0.000 description 11
- 238000005516 engineering process Methods 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 239000002775 capsule Substances 0.000 description 6
- 230000003203 everyday effect Effects 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 5
- 239000004698 Polyethylene Substances 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 229920000573 polyethylene Polymers 0.000 description 4
- 229920001353 Dextrin Polymers 0.000 description 3
- 239000004375 Dextrin Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 102000000340 Glucosyltransferases Human genes 0.000 description 3
- 108010055629 Glucosyltransferases Proteins 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 210000000577 adipose tissue Anatomy 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
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- 238000010579 first pass effect Methods 0.000 description 3
- 235000001727 glucose Nutrition 0.000 description 3
- 125000002791 glucosyl group Chemical class C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 3
- 235000015250 liver sausages Nutrition 0.000 description 3
- 229960003511 macrogol Drugs 0.000 description 3
- 229920001542 oligosaccharide Polymers 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 3
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 2
- 208000017667 Chronic Disease Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000004930 Fatty Liver Diseases 0.000 description 2
- 206010019708 Hepatic steatosis Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
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- 230000017531 blood circulation Effects 0.000 description 2
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- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 2
- WDJHALXBUFZDSR-UHFFFAOYSA-N Acetoacetic acid Natural products CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 108010023302 HDL Cholesterol Proteins 0.000 description 1
- 241001640034 Heteropterys Species 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
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- WOWBFOBYOAGEEA-UHFFFAOYSA-N diafenthiuron Chemical compound CC(C)C1=C(NC(=S)NC(C)(C)C)C(C(C)C)=CC(OC=2C=CC=CC=2)=C1 WOWBFOBYOAGEEA-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to levo carnitine dropping pill for treating adiposis, hepatic disease, which has a high bioavailability, a fast medicine release, a small toxic and deleterious effect, a low utilized cost, and no pollution. The levo carnitine dropping pill takes the levo carnitine or the tartrate and fumarate as medicine active component and can be prepared together with the medicinal carrier as substrate.
Description
Technical field
The present invention relates to a kind of medicine that is used for obesity, hepatopathy, is active pharmaceutical ingredient with L-carnitine (perhaps its esters) particularly, and has the drug composition oral preparation of fat-reducing and inhibition hepatopathy.
Background technology
Current, along with China people's living standard raising, the incidence rate of obesity progressively raises, and nineteen eighty-two, 1989 and 1992 National urban incidence rate overweight and obesity is respectively 9.7%, 12.0% and 14.9%, is progressively trend of rising.Because obesity itself and close with it concurrent hypertension, blood fat disorder, type ii diabetes, coronary heart disease and part tumor etc. have had a strong impact on people's the quality of life and the life-span of shortening.Generally acknowledge that at present body weight reduces by 5%～10% and just can obviously improve the above-mentioned risk factor relevant with obesity, to through keep on a diet and add sharp movement and lose weight effect inadequately significantly the patient need short-term to add to use effective medicine
[1]
According to " Chinese clinical pharmacology and therapeutics " publication king paint, the research article introduction of Chen Bin: obesity is a kind of serious health problem, and in the past decade prevalence has increased by 30%, and about 1/3rd suffer from this disease in U.S. adult.The prevalence of Chinese obesity is now still lacked the Epidemiological study data of accurate large sample, from Shanghai, some data promptings of Hong Kong have the tendency of increasing.Many strong evidence promptings, ameliorate body Beijing South Maxpower Technology Co. Ltd reduces fat harm.The evidence that proposed in NIH technology assessment meeting in 1992 shows, pass through in diet, exercise or the slimming individuality of behavior therapy success in major part, about 1/3～2/3 after 1 year body weight can rebound, and nearly all people can return to original body weight after 5 years.To the physiopathologic further understanding of obesity, can promote everybody and further seek fat new treatment.
Obesity is a kind of chronic disease, and is similar with hypertension concerning many patients, also is a kind of chronic disease that needs long-term treatment, still do not have medicine at present and can cure.The target of Bariatric is to alleviate unnecessary body weight, and suitably loss of weight is good for one's health really, how to seek a kind of not only not only good, the side effect of economy, toleration but also few medicine effectively not only, is the problem of numerous medical personnels' joint research.
L-carnitine (L-carnitinc is to call carnitine in the following text) has another name called vitamin B
T, chemistry L-β-hydroxyl by name-γ-first ammonium butanoic acid is that human body self can synthetic nutrient.The biological action of carnitine relates to energy metabolism, summarizes and gets up to have 3 aspects.1) carrier as the long-chain fat acyl group is transported to long-chain fatty acid in the film outside mitochondrial membrane. play the effect that promotes the fatty acid beta oxidation.2) carrier as the short-chain fat acyl group is transported to short-chain fatty acid (acetyl group, propiono, a chain acyl) outside the film in mitochondrial membrane, plays the effect of regulating mitochondrion CoA/ acetyl-CoA ratio.3) net for catching fish or birds acyl group excessive and non-physiologic group excretes them, plays and gets rid of the metabolism toxicity that body causes because of the acyl group accumulation; Can also promote the oxidation of acetoacetic acid and beta-hydroxybutyric acid, play a driving role in the elimination of ketoboidies with in utilizing.In addition, carnitine tricarboxylic acid cycle, ornithine cycle and essential fatty acid are arachidonic synthetic.
Carnitine plays an important role in mitochondrion fatty acid beta oxidation and tricarboxylic acid cycle, and when carnitine lacks, the fatty acid beta oxidation will be suppressed. can cause fatty infiltration.Zooscopy shows, when ethanol and tetrazotization carbon cause hepatic injury, though the carnitine levels of liver and blood does not reduce, replenishes carnitine and can improve fat metabolic disturbance, corrects fatty liver.Goa KL etc. give chronic hepatitis or the oral carnitine of liver cirrhosis patient, every day 1g, blood plasma free fatty acid concentration reduces after 14 days.Rossics and Polap etc. studies show that, carnitine is to the II type, the IV type, and the V-type hyperlipemia is effective, obeys 3-4g every day, can reduce serum cholesterol and triglyceride levels, increases HDL-C content
[1]
By 37 outstanding swimmers are replenished L-carnitine under normal training condition, and degree of the enclosing situation of change of observing athlete's body fat and variant position is found, under identical meals condition, the experimenter replenished L-carnitine 70 days, its average weight, the skinfold at body fat percentage and six positions all has obvious decline, this illustrates that intravital fat content descends, lose weight, confirmed that from putting into practice L-carnitine has the beta oxidation that promotes fatty acid, help burns unnecessary fat in the body, eliminate unnecessary fat thereby reach, lose weight, to reach salubrious purpose
[2]
Application number is No. 03111770.8, publication number is the oral formulations that No. 1520810 Chinese invention patent discloses a kind of L-carnitine---tablet and capsule, according to this patent specification introduction, this medicine has easy absorption, instant effect, the tangible characteristics of curative effect, is used for the treatment of fatty liver, fat-reducing, treatment cardiovascular and cerebrovascular disease etc.
Owing to reasons such as technologies of preparing, problem such as the oral formulations of most drug exists all that dissolve scattered time limit is long, dissolution is low, absorption is relatively poor, liver sausage first pass effect and bioavailability are lower, thus influence the performance of drug effect, also directly affect therapeutic effect.Simultaneously, conventional tablet or capsule, owing to its production technology, equipment complexity, the production cost height, the cost that makes the patient take is higher.Moreover tablet and capsule can produce bigger dust aborning, and be also relatively more serious to the pollution of environment.
Drop pill is as a kind of novel medicament preparation, and the above many disadvantages that can overcome conventional oral formulations to a great extent and had is a kind of rising new oral formulation.It is investigated that any public technology data or report about levo carnitine dropping pill do not arranged at present as yet.
Summary of the invention
Purpose of the present invention, be to replenish the existing deficiency that is used for the medicine preparation of obesity, hepatopathy, a kind of bioavailability height is provided, release fast, quick produce effects, toxic and side effects is littler, and it is low to take cost, the drug composition oral preparation of production process environmentally safe---levo carnitine dropping pill.
Of the present invention and levo carnitine dropping pill be to be active constituents of medicine with L-carnitine or its esters, with non-ionic surface active agent as substrate, a kind of granular pattern drug composition oral preparation that forms through specific prepared.
Be prepared by the following technical solutions, can obtain levo carnitine dropping pill involved in the present invention:
[preparation method]
1 L-carnitine or its esters (as: L-carnitine-L-tartrate, Carnitine Fumarate)
1.1 L-carnitine---English name L-carnitine, Chinese translation-Kang Li booth, another name-levocarnitine, vitamin B
T
Chemical name---chemistry L-β-hydroxyl by name-γ-first ammonium butanoic acid;
Molecular formula---C
7H
15NO
3
Chemical structural formula:
1.2 L-carnitine-L-tartrate
Chemical name---(R)-two [(3-carboxyl-2-hydroxypropyl) is trimethylammonio]-L-tartrates;
Molecular formula---C
18H
36N
2O
12
1.3 Carnitine Fumarate
Chemical name---(R)-3-carboxyl-2-hydroxy-n, N, the N-trimethyl third ammonium fumarate,
(R)-3 (3-carboxyl-2-hydroxypropyl) is trimethylammonio-fumarate;
Molecular formula---C
11H
19NO
7
2. substrate---Polyethylene Glycol
(2000～20000), one or more the mixture in pharmaceutically suitable carrier such as polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac;
3. proportioning: with g or kg is unit, L-carnitine (or its esters): substrate=1: 1～1: 5;
4. according to the given ratio of prescription, accurately take by weighing each supplementary material, be placed on heating while stirring in the heating container, standby until the fused solution that obtains containing active pharmaceutical ingredient and substrate and/or emulsion and/or suspension;
5. adopt homemade or general drop pill machine (as the TZDW-1 type drop pill machine of Changzheng Tianmin High Science ﹠ Technology Co., Ltd., Beijing's production), and the temperature control system of adjustment drop pill machine, make the water dropper temperature heating of drop pill machine and remain on (50～90) ℃, the temperature cooling of condensing agent also remains on (40～-5) ℃;
6. when treating that the temperature of condensing agent in dropping-pill machine head and the condensation column is stable respectively and reaching desired state of temperature, fused solution and/or the emulsion and/or the suspension that will contain active pharmaceutical ingredient and substrate, place in the water dropper jar of drop pill machine, splash in the condensing agent, condensing agent can be any one in liquid paraffin, methyl-silicone oil, the vegetable oil;
7. will shrink the drop pill taking-up of molding by the outlet of drop pill machine, remove the surface condensation agent, be drying to obtain.
Beneficial effect
Existing L-carnitine oral formulations all is tablet or capsule, clinically treatment obesity, hepatopathy and part cardiovascular and aspect have a wide range of applications.Yet owing to reasons such as technologies of preparing, exist after most of oral formulations are taken that dissolve scattered time limit is long, dissolution is low, absorption is relatively poor, problem such as liver sausage first pass effect and bioavailability are lower, thereby influence giving full play to of drug effect, also directly affect therapeutic effect.Conventional in addition oral formulations uses a large amount of adjuvants, and medicament contg is reduced, and volume increases, and has improved cost accordingly, has increased patient's financial burden.
Of the present invention and levo carnitine dropping pill, utilize substrate such as surfactant polyethylene and L-carnitine (or its esters) to make solid dispersion, make medicine be molecule, colloid or microcrystalline state and be dispersed in the substrate, make the total surface area increase of medicine.And substrate is hydrophilic, and medicine is had wetting action, can make that medicine is rapidly molten to loose into microgranule or solution, thereby makes the dissolving of medicine and absorb and accelerate, thereby has improved bioavailability, has brought into play efficient, quick-acting effects.Compare with other conventional oral formulations, the levo carnitine dropping pill that reaches of the present invention has following beneficial effect:
1. the drop pill that utilizes the solid dispersion technology preparation and get can adopt sublingual administration, and effective ingredient is fully contacted with mucomembranous surface, absorbs by mucomembranous epithelial cell, directly enters blood circulation.Especially sublingual administration administration contacts promptly with saliva and to dissolve rapidly, is absorbed by oral mucosa, directly enters blood circulation without gastrointestinal tract and liver, not only avoided the liver sausage first pass effect, and it is rapid to have brought into play onset, bioavailability height, the advantage that side effect is little.
2. levo carnitine dropping pill production technology, equipment involved in the present invention are simple, and the cycle is short, the automaticity height, and the production efficiency height, production cost can reduce patient's drug cost greatly with below 50% of kind tablet usually.With present commercially available Kombi spy (L-carnitine) capsule is example, and 150 every bottle, preferential price is 165 yuan, the label dose is 3～10/every day, if according to taking 6 calculating every day, take 200 yuan of month needs, the cost of taking medicine of average every day is more than 6 yuan.And the levo carnitine dropping pill that reaches of the present invention, calculate according to identical dosage, according to forecasting of cost and economic analysis, the cost of taking medicine of every day only needs 1.5～2 yuan, (25～33) % for capsule, greatly reduce patient's financial burden, make Most patients all have the ability to use this up to now by universally acknowledged effective slimming medicine.
3. this preparation is by after solid drugs and substrate heating, being melt into liquid state, splash in the not miscible condensed fluid and make, and the stability of drug height, not facile hydrolysis, oxidation is not subject to the influence of crystal formation, thereby guaranteed drug quality, increased stability.
4. the levo carnitine dropping pill that reaches of the present invention, main production process is all carried out under liquid state, and no dust pollution helps labor protection and environmental protection.
The specific embodiment
Now with several groups of specific embodiments, be described further with regard to the preparation method of levo carnitine dropping pill of the present invention.
[first group: with the L-carnitine is the levo carnitine dropping pill that active constituents of medicine is prepared from]
1. adopt the embodiment of single-matrix
1.1 L-carnitine English name---L-carnitine, Chinese translation---Kang Liting;
Another name---levocarnitine, vitamin B
T
Chemical name---chemistry L-β-hydroxyl by name-γ-first ammonium butanoic acid;
1.2 substrate---Polyethylene Glycol
(2000～20000), polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac;
1.3 proportioning---with g or kg is unit, L-carnitine: substrate=1: 1～1: 5;
1.4 the step according to [preparation method] 4～7 is prepared, and can make the levo carnitine dropping pill of different size.
[result of the test]
Test 1: for observe L-carnitine and different substrates when 1: 1 the proportioning prepared levo carnitine dropping pill in qualitative difference, according to 1: 1 ratio, with L-carnitine respectively with Polyethylene Glycol
2000, Polyethylene Glycol
4000, Polyethylene Glycol
6000, Polyethylene Glycol
8000, Polyethylene Glycol
10000, Polyethylene Glycol
20000, pharmaceutically suitable carrier such as polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac matches, be prepared according to the step of stipulating in the preparation method, can obtain 15 pharmaceutical compositions experiments that contain L-carnitine and different substrates, and obtain 15 groups of different experimental results and see Table 1.
Test 2: for observe L-carnitine and different substrates when 1: 2 the proportioning prepared levo carnitine dropping pill in qualitative difference, according to 1: 2 ratio, with L-carnitine respectively with Polyethylene Glycol
2000, Polyethylene Glycol
4000, Polyethylene Glycol
6000, Polyethylene Glycol
8000, Polyethylene Glycol
10000, Polyethylene Glycol
20000, pharmaceutically suitable carrier such as polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac matches, be prepared according to the step of stipulating in the preparation method, can obtain 15 pharmaceutical compositions experiments that contain L-carnitine and different substrates, and obtain 15 groups of different experimental results and see Table 1.
Test 3: for observe L-carnitine and different substrates when 1: 5 the proportioning prepared levo carnitine dropping pill in qualitative difference, according to 1: 5 ratio, with L-carnitine respectively with Polyethylene Glycol
2000, Polyethylene Glycol
4000, Polyethylene Glycol
6000, Polyethylene Glycol
8000, Polyethylene Glycol
10000, Polyethylene Glycol
20000, pharmaceutically suitable carrier such as polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac matches, be prepared according to the step of stipulating in the preparation method, can obtain 15 pharmaceutical compositions experiments that contain L-carnitine and different substrates, and obtain 15 groups of different experimental results and see Table 1.
2. adopt the embodiment of two kinds of adjuvants as composite interstitial substance
2.1 L-carnitine English name---L-carnitine, Chinese translation---Kang Liting;
Another name---levocarnitine, vitamin B
T
Chemical name---chemistry L-β-hydroxyl by name-γ-first ammonium butanoic acid;
2.2 substrate:
Polyethylene Glycol---English name Macrogol,
Polyoxyethylene stearate 40 esters---English name Polyoxyl (40) Stearate,
Molecular formula is with C
17H
35COO (CH
2CH
2O)
nH represents that n is about 40,
Poloxamer---English name Poloxamer, polyoxyethylene poly-oxygen propylene aether,
Molecular formula HO (C
2H
4O)
a(C
3H
6O)
b(C
2H
4O)
cH,
The sodium salt of the starch carboxymethyl ester that carboxymethyl starch sodium---English name Carboxymethylstach Sodium, starch generates with the monoxone effect under alkali condition,
Betacyclodextrin---English name Betacyclodextrin, molecular formula C
6H
10O
5, this product is that ring dextrin glucosyl transferase acts on 7 glucoses that starch generates with α-1, the bonded cyclic oligosaccharide of 4-glycosidic bond;
2.3 proportioning---with g or kg is unit, by weight, and drug extract: substrate=1: 1～1: 5;
2.4 the process that provides according to [preparation method] 4～7 is prepared, and can make the levo carnitine dropping pill of different size.
[result of the test]
Test 4: in order to observe the mass discrepancy of L-carnitine and composite interstitial substance prepared levo carnitine dropping pill when 1: 1 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 1 mixed evenly as mixed-matrix, according to 1: 1 ratio L-carnitine is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 4.
Test 5: in order to observe the mass discrepancy of L-carnitine and composite interstitial substance prepared levo carnitine dropping pill when 1: 2 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 1 mixed evenly as mixed-matrix, according to 1: 2 ratio L-carnitine is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 5.
Test 6: in order to observe the mass discrepancy of L-carnitine and composite interstitial substance prepared levo carnitine dropping pill when 1: 5 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 1 mixed evenly as mixed-matrix, according to 1: 5 ratio L-carnitine is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 6.
Test 7: in order to observe the mass discrepancy of L-carnitine and composite interstitial substance prepared levo carnitine dropping pill when 1: 1 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 5 mixed evenly as mixed-matrix, according to 1: 1 ratio L-carnitine is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 7.
Test 8: in order to observe the mass discrepancy of L-carnitine and composite interstitial substance prepared levo carnitine dropping pill when 1: 2 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 5 mixed evenly as mixed-matrix, according to 1: 2 ratio L-carnitine is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 8.
Test 9: in order to observe the mass discrepancy of L-carnitine and composite interstitial substance prepared levo carnitine dropping pill when 1: 5 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 5 mixed evenly as mixed-matrix, according to 1: 5 ratio L-carnitine is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 9.
Test 10: in order to observe the mass discrepancy of L-carnitine and composite interstitial substance prepared levo carnitine dropping pill when 1: 1 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 10 mixed evenly as mixed-matrix, according to 1: 1 ratio L-carnitine is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 10.
Test 11: in order to observe the mass discrepancy of L-carnitine and composite interstitial substance prepared levo carnitine dropping pill when 1: 2 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 10 mixed evenly as mixed-matrix, according to 1: 2 ratio L-carnitine is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 11.
Test 12: in order to observe the mass discrepancy of L-carnitine and composite interstitial substance prepared levo carnitine dropping pill when 1: 5 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 10 mixed evenly as mixed-matrix, according to 1: 5 ratio L-carnitine is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 12.
The group practices of table 1 L-carnitine and single-matrix
(L-carnitine: substrate=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyethylene Glycol 2000 | ????50.0 | ????65 | ????＜30 | ????＞10 | + |
| Polyethylene Glycol 4000 | ????50.0 | ????74 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 6000 | ????50.0 | ????74 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 8000 | ????50.0 | ????76 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 10000 | ????50.0 | ????78 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 20000 | ????50.0 | ????77 | ????＜30 | ????＞10 | ++ |
| Polyoxyethylene stearate 40 esters | ????50.0 | ????74 | ????＜30 | ????＞10 | ++ |
| Betacyclodextrin | ????50.0 | ????70 | ????＜30 | ????＞10 | + |
| Poloxamer | ????50.0 | ????75 | ????＜30 | ????＞10 | ++ |
| Carboxymethyl starch sodium | ????50.0 | ????73 | ????＜30 | ????＞10 | + |
| Sodium lauryl sulphate | ????50.0 | ????69 | ????＞30 | ????＞10 | ++ |
| Stearic acid | ????50.0 | ????56 | ????＞30 | ????＞10 | ++ |
| Sodium stearate | ????50.0 | ????55 | ????＞30 | ????＞10 | ++ |
| Glycerin gelatine | ????50.0 | ????57 | ????＞30 | ????＞10 | + |
| Lac | ????50.0 | ????56 | ????＞30 | ????＞10 | + |
The group practices of table 2 L-carnitine and single-matrix
(L-carnitine: substrate=1: 2)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyethylene Glycol 2000 | ????33.3 | ????82 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 4000 | ????33.3 | ????87 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 6000 | ????33.3 | ????90 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 8000 | ????33.3 | ????92 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 10000 | ????33.3 | ????92 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 20000 | ????33.3 | ????92 | ????＜30 | ????＜10 | +++ |
| Polyoxyethylene stearate 40 esters | ????33.3 | ????90 | ????＜30 | ????＜10 | ++ |
| Betacyclodextrin | ????33.3 | ????83 | ????＜30 | ????＞10 | ++ |
| Poloxamer | ????33.3 | ????90 | ????＜30 | ????＜10 | +++ |
| Carboxymethyl starch sodium | ????33.3 | ????86 | ????＜30 | ????＜10 | +++ |
| Sodium lauryl sulphate | ????33.3 | ????81 | ????＜30 | ????＞10 | ++ |
| Stearic acid | ????33.3 | ????79 | ????＞30 | ????＞10 | +++ |
| Sodium stearate | ????33.3 | ????79 | ????＞30 | ????＞10 | +++ |
| Glycerin gelatine | ????33.3 | ????74 | ????＞30 | ????＞10 | +++ |
| Lac | ????33.3 | ????73 | ????＞30 | ????＞10 | +++ |
The group practices of table 3 L-carnitine and single-matrix
(L-carnitine: substrate=1: 5)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyethylene Glycol 2000 | ????16.7 | ????83 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 4000 | ????16.7 | ????90 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 6000 | ????16.7 | ????92 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 8000 | ????16.7 | ????93 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 10000 | ????16.7 | ????91 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 20000 | ????16.7 | ????91 | ????＜30 | ????＜10 | +++ |
| Polyoxyethylene stearate 40 esters | ????16.7 | ????92 | ????＜30 | ????＜10 | ++ |
| Betacyclodextrin | ????16.7 | ????87 | ????＜30 | ????＜10 | ++ |
| Poloxamer | ????16.7 | ????91 | ????＜30 | ????＜10 | +++ |
| Carboxymethyl starch sodium | ????16.7 | ????90 | ????＜30 | ????＜10 | +++ |
| Sodium lauryl sulphate | ????16.7 | ????81 | ????＜30 | ????＞10 | +++ |
| Stearic acid | ????16.7 | ????82 | ????＞30 | ????＞10 | +++ |
| Sodium stearate | ????16.7 | ????83 | ????＞30 | ????＞10 | +++ |
| Glycerin gelatine | ????16.7 | ????77 | ????＞30 | ????＞10 | +++ |
| Lac | ????16.7 | ????76 | ????＞30 | ????＞10 | +++ |
The group practices of table 4 L-carnitine and mixed-matrix
(L-carnitine: mixed-matrix=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 1 | ????50 ? | ????85 ? | ????＜30 ? | ????＞10 ? | ++ ? |
| Poloxamer: Polyethylene Glycol=1: 1 | ????50 ? | ????83 ? | ????＜30 ? | ????＞10 ? | ++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 1 | ????50 ? | ????80 ? | ????＜30 ? | ????＞10 ? | ++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 1 | ????50 ? | ????74 ? | ????＜30 ? | ????＞10 ? | + ? |
The group practices of table 5 L-carnitine and mixed-matrix
(L-carnitine: mixed-matrix=1: 2)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 1 | ????33.3 ? | ????89 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 1 | ????33.3 ? | ????89 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 1 | ????33.3 ? | ????87 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 1 | ????33.3 ? | ????83 ? | ????＜30 ? | ????＞10 ? | ++ ? |
The group practices of table 6 L-carnitine and mixed-matrix
(L-carnitine: mixed-matrix=1: 5)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 1 | ????16.7 ? | ????88 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 1 | ????16.7 ? | ????88 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 1 | ????16.7 ? | ????84 ? | ????＜30 ? | ????＞10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 1 | ????16.7 ? | ????81 ? | ????＜30 ? | ????＞10 ? | +++ ? |
The group practices of table 7 L-carnitine and mixed-matrix
(L-carnitine: mixed-matrix=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 5 | ????50 ? | ????90 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 5 | ????50 ? | ????91 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 5 | ????50 ? | ????91 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 5 | ????50 ? | ????87 ? | ????＜30 ? | ????＜10 ? | ++ ? |
The group practices of table 8 L-carnitine and mixed-matrix
(L-carnitine: mixed-matrix=1: 2)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 5 | ????33.3 ? | ????93 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 5 | ????33.3 ? | ????93 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 5 | ????33.3 ? | ????91 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 5 | ????33.3 ? | ????88 ? | ????＜30 ? | ????＜10 ? | +++ ? |
The group practices of table 9 L-carnitine and mixed-matrix
(L-carnitine: mixed-matrix=1: 5)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 5 | ????16.7 ? | ????92 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 5 | ????16.7 ? | ????92 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 5 | ????16.7 ? | ????92 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 5 | ????16.7 ? | ????90 ? | ????＜30 ? | ????＜10 ? | +++ ? |
The group practices of table 10 L-carnitine and mixed-matrix
(L-carnitine: mixed-matrix=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 10 | ????50 ? | ????92 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 10 | ????50 ? | ????90 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 10 | ????50 ? | ????89 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 10 | ????50 ? | ????83 ? | ????＜30 ? | ????＞10 ? | +++ ? |
The group practices of table 11 L-carnitine and mixed-matrix
(L-carnitine: mixed-matrix=1: 2)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 10 | ????33.3 ? | ????92 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 10 | ????33.3 ? | ????93 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 10 | ????33.3 ? | ????90 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 10 | ????33.3 ? | ????86 ? | ????＜30 ? | ????＜10 ? | +++ ? |
The group practices of table 12 L-carnitine and mixed-matrix
(L-carnitine: mixed-matrix=1: 5)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 10 | ????16.7 ? | ????93 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 10 | ????16.7 ? | ????92 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 10 | ????16.7 ? | ????91 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 10 | ????16.7 ? | ????89 ? | ????＜30 ? | ????＜10 ? | +++ ? |
[second group: with the L-carnitine-L-tartrate is the levo carnitine dropping pill that active constituents of medicine is prepared from]
1. adopt the embodiment of single-matrix
1.1 L-carnitine-L-tartrate chemical name---(R)-two [(3-carboxyl-2-hydroxypropyl) is trimethylammonio]-L-tartrates;
1.2 substrate---Polyethylene Glycol
(2000～20000), polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac;
1.3 proportioning---with g or kg is unit, L-carnitine: substrate=1: 1～1: 5;
1.4 the step according to [preparation method] 4～7 is prepared, can make with the L-carnitine-L-tartrate is the levo carnitine dropping pill of the different size of active pharmaceutical ingredient.
[result of the test]
Test 1: for observe L-carnitine-L-tartrate and different substrates when 1: 1 the proportioning prepared levo carnitine dropping pill in qualitative difference, according to 1: 1 ratio, with L-carnitine-L-tartrate respectively with Polyethylene Glycol
2000, Polyethylene Glycol
4000, Polyethylene Glycol
6000, Polyethylene Glycol
8000, Polyethylene Glycol
10000, Polyethylene Glycol
20000, pharmaceutically suitable carrier such as polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac matches, be prepared according to the step of stipulating in the preparation method, can obtain 15 pharmaceutical compositions experiments that contain L-carnitine-L-tartrate and different substrates, and obtain 15 groups of different experimental results and see Table 1.
Test 2: for observe L-carnitine-L-tartrate and different substrates when 1: 2 the proportioning prepared levo carnitine dropping pill in qualitative difference, according to 1: 2 ratio, with L-carnitine-L-tartrate respectively with Polyethylene Glycol
2000, Polyethylene Glycol
4000, Polyethylene Glycol
6000, Polyethylene Glycol
8000, Polyethylene Glycol
10000, Polyethylene Glycol
20000, pharmaceutically suitable carrier such as polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac matches, be prepared according to the step of stipulating in the preparation method, can obtain 15 pharmaceutical compositions experiments that contain L-carnitine-L-tartrate and different substrates, and obtain 15 groups of different experimental results and see Table 2.
Test 3: for observe L-carnitine-L-tartrate and different substrates when 1: 3 the proportioning prepared levo carnitine dropping pill in qualitative difference, according to 1: 3 ratio, with L-carnitine-L-tartrate respectively with Polyethylene Glycol
2000, Polyethylene Glycol
4000, Polyethylene Glycol
6000, Polyethylene Glycol
8000, Polyethylene Glycol
10000, Polyethylene Glycol
20000, pharmaceutically suitable carrier such as polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac matches, be prepared according to the step of stipulating in the preparation method, can obtain 15 pharmaceutical compositions experiments that contain L-carnitine-L-tartrate and different substrates, and obtain 15 groups of different experimental results and see Table 3.
2. adopt the embodiment of two kinds of adjuvants as composite interstitial substance
2.1 L-carnitine-L-tartrate chemical name---(R)-two [(3-carboxyl-2-hydroxypropyl) is trimethylammonio]-L-tartrates;
2.2 substrate:
Polyethylene Glycol---English name Macrogol,
Polyoxyethylene stearate 40 esters---English name Polyoxyl (40) Stearate,
Molecular formula is with C
17H
35COO (CH
2CH
2O)
nH represents that n is about 40,
Poloxamer---English name Poloxamer, polyoxyethylene poly-oxygen propylene aether,
Molecular formula HO (C
2H
4O)
a(C
3H
6O)
b(C
2H
4O)
cH,
The sodium salt of the starch carboxymethyl ester that carboxymethyl starch sodium---English name Carboxymethylstach Sodium, starch generates with the monoxone effect under alkali condition,
Betacyclodextrin---English name Betacyclodextrin, molecular formula C
6H
10O
5, this product is that ring dextrin glucosyl transferase acts on 7 glucoses that starch generates with α-1, the bonded cyclic oligosaccharide of 4-glycosidic bond;
2.3 proportioning---with g or kg is unit, by weight, and drug extract: substrate=1: 1～1: 5;
2.4 the step according to [preparation method] 4～7 is prepared, can make with the L-carnitine-L-tartrate is the levo carnitine dropping pill of the different size of active pharmaceutical ingredient.
[result of the test]
Test 4: in order to observe L-carnitine-L-tartrate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 1 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 1 mixed evenly as mixed-matrix, according to 1: 1 ratio L-carnitine-L-tartrate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine-L-tartrate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 4.
Test 5: in order to observe L-carnitine-L-tartrate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 2 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 1 mixed evenly as mixed-matrix, according to 1: 2 ratio L-carnitine-L-tartrate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine-L-tartrate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 5.
Test 6: in order to observe L-carnitine-L-tartrate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 5 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 1 mixed evenly as mixed-matrix, according to 1: 5 ratio L-carnitine-L-tartrate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine-L-tartrate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 6.
Test 7: in order to observe L-carnitine-L-tartrate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 1 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 5 mixed evenly as mixed-matrix, according to 1: 1 ratio L-carnitine-L-tartrate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine-L-tartrate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 7.
Test 8: in order to observe L-carnitine-L-tartrate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 2 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 5 mixed evenly as mixed-matrix, according to 1: 2 ratio L-carnitine-L-tartrate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine-L-tartrate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 8.
Test 9: in order to observe L-carnitine-L-tartrate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 5 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 5 mixed evenly as mixed-matrix, according to 1: 5 ratio L-carnitine-L-tartrate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine-L-tartrate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 9.
Test 10: in order to observe L-carnitine-L-tartrate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 1 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 10 mixed evenly as mixed-matrix, according to 1: 1 ratio L-carnitine-L-tartrate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine-L-tartrate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 10.
Test 11: in order to observe L-carnitine-L-tartrate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 2 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 10 mixed evenly as mixed-matrix, according to 1: 2 ratio L-carnitine-L-tartrate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine-L-tartrate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 11.
Test 12: in order to observe L-carnitine-L-tartrate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 5 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 10 mixed evenly as mixed-matrix, according to 1: 5 ratio L-carnitine-L-tartrate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that L-carnitine-L-tartrate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 12.
The group practices of table 1 L-carnitine-L-tartrate and single-matrix
(L-carnitine-L-tartrate: substrate=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyethylene Glycol 2000 | ????50.0 | ????64 | ????＜30 | ????＞10 | + |
| Polyethylene Glycol 4000 | ????50.0 | ????75 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 6000 | ????50.0 | ????76 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 8000 | ????50.0 | ????75 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 10000 | ????50.0 | ????78 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 20000 | ????50.0 | ????77 | ????＜30 | ????＞10 | ++ |
| Polyoxyethylene stearate 40 esters | ????50.0 | ????75 | ????＜30 | ????＞10 | ++ |
| Betacyclodextrin | ????50.0 | ????70 | ????＜30 | ????＞10 | + |
| Poloxamer | ????50.0 | ????78 | ????＜30 | ????＞10 | ++ |
| Carboxymethyl starch sodium | ????50.0 | ????74 | ????＜30 | ????＞10 | + |
| Sodium lauryl sulphate | ????50.0 | ????69 | ????＞30 | ????＞10 | ++ |
| Stearic acid | ????50.0 | ????55 | ????＞30 | ????＞10 | ++ |
| Sodium stearate | ????50.0 | ????56 | ????＞30 | ????＞10 | ++ |
| Glycerin gelatine | ????50.0 | ????58 | ????＞30 | ????＞10 | + |
| Lac | ????50.0 | ????56 | ????＞30 | ????＞10 | + |
The group practices of table 2 L-carnitine-L-tartrate and single-matrix
(L-carnitine-L-tartrate: substrate=1: 2)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyethylene Glycol 2000 | ????33.3 | ????80 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 4000 | ????33.3 | ????87 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 6000 | ????33.3 | ????90 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 8000 | ????33.3 | ????91 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 10000 | ????33.3 | ????91 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 20000 | ????33.3 | ????92 | ????＜30 | ????＜10 | +++ |
| Polyoxyethylene stearate 40 esters | ????33.3 | ????90 | ????＜30 | ????＜10 | ++ |
| Betacyclodextrin | ????33.3 | ????80 | ????＜30 | ????＞10 | ++ |
| Poloxamer | ????33.3 | ????91 | ????＜30 | ????＜10 | +++ |
| Carboxymethyl starch sodium | ????33.3 | ????87 | ????＜30 | ????＜10 | +++ |
| Sodium lauryl sulphate | ????33.3 | ????82 | ????＜30 | ????＞10 | ++ |
| Stearic acid | ????33.3 | ????78 | ????＞30 | ????＞10 | +++ |
| Sodium stearate | ????33.3 | ????78 | ????＞30 | ????＞10 | +++ |
| Glycerin gelatine | ????33.3 | ????73 | ????＞30 | ????＞10 | +++ |
| Lac | ????33.3 | ????73 | ????＞30 | ????＞10 | +++ |
The group practices of table 3 L-carnitine-L-tartrate and single-matrix
(L-carnitine-L-tartrate: substrate=1: 5)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyethylene Glycol 2000 | ????16.7 | ????84 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 4000 | ????16.7 | ????90 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 6000 | ????16.7 | ????93 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 8000 | ????16.7 | ????93 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 10000 | ????16.7 | ????93 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 20000 | ????16.7 | ????94 | ????＜30 | ????＜10 | +++ |
| Polyoxyethylene stearate 40 esters | ????16.7 | ????93 | ????＜30 | ????＜10 | ++ |
| Betacyclodextrin | ????16.7 | ????87 | ????＜30 | ????＜10 | ++ |
| Poloxamer | ????16.7 | ????93 | ????＜30 | ????＜10 | +++ |
| Carboxymethyl starch sodium | ????16.7 | ????90 | ????＜30 | ????＜10 | +++ |
| Sodium lauryl sulphate | ????16.7 | ????81 | ????＜30 | ????＞10 | +++ |
| Stearic acid | ????16.7 | ????81 | ????＞30 | ????＞10 | +++ |
| Sodium stearate | ????16.7 | ????82 | ????＞30 | ????＞10 | +++ |
| Glycerin gelatine | ????16.7 | ????77 | ????＞30 | ????＞10 | +++ |
| Lac | ????16.7 | ????76 | ????＞30 | ????＞10 | +++ |
The group practices of table 4 L-carnitine-L-tartrate and mixed-matrix
(L-carnitine-L-tartrate: mixed-matrix=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 1 | ????50 ? | ????82 ? | ????＜30 ? | ????＞10 ? | ++ ? |
| Poloxamer: Polyethylene Glycol=1: 1 | ????50 ? | ????80 ? | ????＜30 ? | ????＞10 ? | ++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 1 | ????50 ? | ????80 ? | ????＜30 ? | ????＞10 ? | ++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 1 | ????50 ? | ????76 ? | ????＜30 ? | ????＞10 ? | + ? |
The group practices of table 5 L-carnitine-L-tartrate and mixed-matrix
(L-carnitine-L-tartrate: mixed-matrix=1: 2)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 1 | ????33.3 ? | ????89 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 1 | ????33.3 ? | ????89 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 1 | ????33.3 ? | ????87 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 1 | ????33.3 ? | ????84 ? | ????＜30 ? | ????＞10 ? | ++ ? |
The group practices of table 6 L-carnitine-L-tartrate and mixed-matrix
(L-carnitine-L-tartrate: mixed-matrix=1: 5)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 1 | ????16.7 ? | ????88 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 1 | ????16.7 ? | ????88 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 1 | ????16.7 ? | ????84 ? | ????＜30 ? | ????＞10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 1 | ????16.7 ? | ????82 ? | ????＜30 ? | ????＞10 ? | +++ ? |
The group practices of table 7 L-carnitine-L-tartrate and mixed-matrix
(L-carnitine-L-tartrate: mixed-matrix=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 5 | ????50 ? | ????91 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 5 | ????50 ? | ????91 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 5 | ????50 ? | ????90 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 5 | ????50 ? | ????87 ? | ????＜30 ? | ????＜10 ? | ++ ? |
The group practices of table 8 L-carnitine-L-tartrate and mixed-matrix
(L-carnitine-L-tartrate: mixed-matrix=1: 2)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 5 | ????33.3 ? | ????93 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 5 | ????33.3 ? | ????93 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 5 | ????33.3 ? | ????92 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 5 | ????33.3 ? | ????90 ? | ????＜30 ? | ????＜10 ? | +++ ? |
The group practices of table 9 L-carnitine-L-tartrate and mixed-matrix
(L-carnitine-L-tartrate: mixed-matrix=1: 5)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 5 | ????16.7 ? | ????93 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 5 | ????16.7 ? | ????93 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 5 | ????16.7 ? | ????93 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 5 | ????16.7 ? | ????90 ? | ????＜30 ? | ????＜10 ? | +++ ? |
The group practices of table 10 L-carnitine-L-tartrate and mixed-matrix
(L-carnitine-L-tartrate: mixed-matrix=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 10 | ????50 ? | ????90 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 10 | ????50 ? | ????91 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 10 | ????50 ? | ????86 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 10 | ????50 ? | ????84 ? | ????＜30 ? | ????＞10 ? | +++ ? |
The group practices of table 11 L-carnitine-L-tartrate and mixed-matrix
(L-carnitine-L-tartrate: mixed-matrix=1: 2)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 10 | ????33.3 ? | ????92 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 10 | ????33.3 ? | ????92 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 10 | ????33.3 ? | ????91 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 10 | ????33.3 ? | ????87 ? | ????＜30 ? | ????＜10 ? | +++ ? |
The group practices of table 12 L-carnitine-L-tartrate and mixed-matrix
(L-carnitine-L-tartrate: mixed-matrix=1: 5)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 10 | ????16.7 ? | ????92 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 10 | ????16.7 ? | ????92 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 10 | ????16.7 ? | ????91 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 10 | ????16.7 ? | ????90 ? | ????＜30 ? | ????＜10 ? | +++ ? |
[the 3rd group: with the Carnitine Fumarate is the levo carnitine dropping pill that active constituents of medicine is prepared from]
1. adopt the embodiment of single-matrix
1.1 Carnitine Fumarate chemical name:
(R)-and 3-carboxyl-2-hydroxy-n, N, the N-trimethyl third ammonium fumarate;
(R)-3 (3-carboxyl-2-hydroxypropyl) is trimethylammonio-fumarate;
1.2 substrate---Polyethylene Glycol
(2000～20000), polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac;
1.3 proportioning---with g or kg is unit, L-carnitine: substrate=1: 1～1: 5;
1.4 the step according to [preparation method] 4～7 is prepared, can make with the Carnitine Fumarate is the levo carnitine dropping pill of the different size of active pharmaceutical ingredient.
[result of the test]
Test 1: for observe Carnitine Fumarate and different substrates when 1: 1 the proportioning prepared levo carnitine dropping pill in qualitative difference, according to 1: 1 ratio, with Carnitine Fumarate respectively with Polyethylene Glycol
2000, Polyethylene Glycol
4000, Polyethylene Glycol
6000, Polyethylene Glycol
8000, Polyethylene Glycol
10000, Polyethylene Glycol
20000, pharmaceutically suitable carrier such as polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac matches, be prepared according to the step of stipulating in the preparation method, can obtain 15 pharmaceutical compositions experiments that contain Carnitine Fumarate and different substrates, and obtain 15 groups of different experimental results and see Table 1.
Test 2: for observe Carnitine Fumarate and different substrates when 1: 2 the proportioning prepared levo carnitine dropping pill in qualitative difference, according to 1: 2 ratio, with Carnitine Fumarate respectively with Polyethylene Glycol
2000, Polyethylene Glycol
4000, Polyethylene Glycol
6000, Polyethylene Glycol
8000, Polyethylene Glycol
10000, Polyethylene Glycol
20000, pharmaceutically suitable carrier such as polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac matches, be prepared according to the step of stipulating in the preparation method, can obtain 15 pharmaceutical compositions experiments that contain Carnitine Fumarate and different substrates, and obtain 15 groups of different experimental results and see Table 2.
Test 3: for observe Carnitine Fumarate and different substrates when 1: 5 the proportioning prepared levo carnitine dropping pill in qualitative difference, according to 1: 5 ratio, with Carnitine Fumarate respectively with Polyethylene Glycol
2000, Polyethylene Glycol
4000, Polyethylene Glycol
6000, Polyethylene Glycol
8000, Polyethylene Glycol
10000, Polyethylene Glycol
20000, pharmaceutically suitable carrier such as polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac matches, be prepared according to the step of stipulating in the preparation method, can obtain 15 pharmaceutical compositions experiments that contain Carnitine Fumarate and different substrates, and obtain 15 groups of different experimental results and see Table 3.
2. adopt the embodiment of two kinds of adjuvants as composite interstitial substance
2.1 Carnitine Fumarate chemical name:
(R)-and 3-carboxyl-2-hydroxy-n, N, the N-trimethyl third ammonium fumarate,
(R)-3 (3-carboxyl-2-hydroxypropyl) is trimethylammonio-fumarate;
2.2 substrate:
Polyethylene Glycol---English name Macrogol,
Polyoxyethylene stearate 40 esters---English name Polyoxyl (40) Stearate,
Molecular formula is with C
17H
35COO (CH
2CH
2O)
nH represents that n is about 40,
Poloxamer---English name Poloxamer, polyoxyethylene poly-oxygen propylene aether,
Molecular formula HO (C
2H
4O)
a(C
3H
6O)
b(C
2H
4O)
cH,
The sodium salt of the starch carboxymethyl ester that carboxymethyl starch sodium---English name Carboxymethylstach Sodium, starch generates with the monoxone effect under alkali condition,
Betacyclodextrin---English name Betacyclodextrin, molecular formula C
6H
10O
5, this product is that ring dextrin glucosyl transferase acts on 7 glucoses that starch generates with α-1, the bonded cyclic oligosaccharide of 4-glycosidic bond;
2.3 proportioning---with g or kg is unit, by weight, and drug extract: substrate=1: 1～1: 5;
2.4 the step according to [preparation method] 4～7 is prepared, can make with the Carnitine Fumarate is the levo carnitine dropping pill of the different size of active pharmaceutical ingredient.
[result of the test]
Test 4: in order to observe Carnitine Fumarate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 1 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 1 mixed evenly as mixed-matrix, according to 1: 1 ratio Carnitine Fumarate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that Carnitine Fumarate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 4.
Test 5: in order to observe Carnitine Fumarate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 2 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 1 mixed evenly as mixed-matrix, according to 1: 2 ratio Carnitine Fumarate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that Carnitine Fumarate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 4.
Test 6: in order to observe Carnitine Fumarate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 5 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 1 mixed evenly as mixed-matrix, according to 1: 5 ratio Carnitine Fumarate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that Carnitine Fumarate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 6.
Test 7: in order to observe Carnitine Fumarate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 1 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 5 mixed evenly as mixed-matrix, according to 1: 1 ratio Carnitine Fumarate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that Carnitine Fumarate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 7.
Test 8: in order to observe Carnitine Fumarate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 2 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 5 mixed evenly as mixed-matrix, according to 1: 2 ratio Carnitine Fumarate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that Carnitine Fumarate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 8.
Test 9: in order to observe Carnitine Fumarate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 5 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 5 mixed evenly as mixed-matrix, according to 1: 5 ratio Carnitine Fumarate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that Carnitine Fumarate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 9.
Test 10: in order to observe Carnitine Fumarate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 1 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 10 mixed evenly as mixed-matrix, according to 1: 1 ratio Carnitine Fumarate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that Carnitine Fumarate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 10.
Test 11: in order to observe Carnitine Fumarate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 2 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 10 mixed evenly as mixed-matrix, according to 1: 2 ratio Carnitine Fumarate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that Carnitine Fumarate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 11.
Test 12: in order to observe Carnitine Fumarate and composite interstitial substance obtained levo carnitine dropping pill mass discrepancy when 1: 5 the proportioning, with polyoxyethylene stearate 40 esters, poloxamer, carboxymethyl starch sodium, 4 kinds of carriers such as betacyclodextrin respectively with Polyethylene Glycol with 1: 10 mixed evenly as mixed-matrix, according to 1: 5 ratio Carnitine Fumarate is mixed with 4 kinds of different composite matrix phases respectively again and make evenly, be prepared according to the step of stipulating in the preparation method, can obtain the experiment of 4 pharmaceutical compositions that Carnitine Fumarate and composite interstitial substance constituted, and obtain 4 groups of different experiments and the results are shown in Table 12.
The group practices of table 1 Carnitine Fumarate and single-matrix
(Carnitine Fumarate: substrate=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyethylene Glycol 2000 | ????50.0 | ????60 | ????＜30 | ????＞10 | + |
| Polyethylene Glycol 4000 | ????50.0 | ????72 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 6000 | ????50.0 | ????74 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 8000 | ????50.0 | ????74 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 10000 | ????50.0 | ????76 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 20000 | ????50.0 | ????78 | ????＜30 | ????＞10 | ++ |
| Polyoxyethylene stearate 40 esters | ????50.0 | ????74 | ????＜30 | ????＞10 | ++ |
| Betacyclodextrin | ????50.0 | ????70 | ????＜30 | ????＞10 | + |
| Poloxamer | ????50.0 | ????77 | ????＜30 | ????＞10 | ++ |
| Carboxymethyl starch sodium | ????50.0 | ????74 | ????＜30 | ????＞10 | + |
| Sodium lauryl sulphate | ????50.0 | ????68 | ????＞30 | ????＞10 | ++ |
| Stearic acid | ????50.0 | ????57 | ????＞30 | ????＞10 | ++ |
| Sodium stearate | ????50.0 | ????57 | ????＞30 | ????＞10 | ++ |
| Glycerin gelatine | ????50.0 | ????55 | ????＞30 | ????＞10 | + |
| Lac | ????50.0 | ????56 | ????＞30 | ????＞10 | + |
The group practices of table 2 Carnitine Fumarate and single-matrix
(Carnitine Fumarate: substrate=1: 2)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyethylene Glycol 2000 | ????33.3 | ????80 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 4000 | ????33.3 | ????86 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 6000 | ????33.3 | ????90 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 8000 | ????33.3 | ????91 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 10000 | ????33.3 | ????91 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 20000 | ????33.3 | ????92 | ????＜30 | ????＜10 | +++ |
| Polyoxyethylene stearate 40 esters | ????33.3 | ????89 | ????＜30 | ????＜10 | ++ |
| Betacyclodextrin | ????33.3 | ????84 | ????＜30 | ????＞10 | ++ |
| Poloxamer | ????33.3 | ????91 | ????＜30 | ????＜10 | +++ |
| Carboxymethyl starch sodium | ????33.3 | ????86 | ????＜30 | ????＜10 | +++ |
| Sodium lauryl sulphate | ????33.3 | ????80 | ????＜30 | ????＞10 | ++ |
| Stearic acid | ????33.3 | ????77 | ????＞30 | ????＞10 | +++ |
| Sodium stearate | ????33.3 | ????78 | ????＞30 | ????＞10 | +++ |
| Glycerin gelatine | ????33.3 | ????72 | ????＞30 | ????＞10 | +++ |
| Lac | ????33.3 | ????73 | ????＞30 | ????＞10 | +++ |
The group practices of table 3 Carnitine Fumarate and single-matrix
(Carnitine Fumarate: substrate=1: 5)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyethylene Glycol 2000 | ????16.7 | ????82 | ????＜30 | ????＞10 | ++ |
| Polyethylene Glycol 4000 | ????16.7 | ????88 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 6000 | ????16.7 | ????91 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 8000 | ????16.7 | ????92 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 10000 | ????16.7 | ????92 | ????＜30 | ????＜10 | +++ |
| Polyethylene Glycol 20000 | ????16.7 | ????93 | ????＜30 | ????＜10 | +++ |
| Polyoxyethylene stearate 40 esters | ????16.7 | ????93 | ????＜30 | ????＜10 | ++ |
| Betacyclodextrin | ????16.7 | ????87 | ????＜30 | ????＜10 | ++ |
| Poloxamer | ????16.7 | ????92 | ????＜30 | ????＜10 | +++ |
| Carboxymethyl starch sodium | ????16.7 | ????89 | ????＜30 | ????＜10 | +++ |
| Sodium lauryl sulphate | ????16.7 | ????81 | ????＜30 | ????＞10 | +++ |
| Stearic acid | ????16.7 | ????82 | ????＞30 | ????＞10 | +++ |
| Sodium stearate | ????16.7 | ????82 | ????＞30 | ????＞10 | +++ |
| Glycerin gelatine | ????16.7 | ????79 | ????＞30 | ????＞10 | +++ |
| Lac | ????16.7 | ????78 | ????＞30 | ????＞10 | +++ |
The group practices of table 4 Carnitine Fumarate and mixed-matrix
(Carnitine Fumarate: mixed-matrix=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 1 | ????50 ? | ????80 ? ?? | ????＜30 ? | ????＞10 ? | ++ ? |
| Poloxamer: Polyethylene Glycol=1: 1 | ????50 ? | ????80 ? | ????＜30 ? | ????＞10 ? | ++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 1 | ????50 ? | ????78 ? | ????＜30 ? | ????＞10 ? | ++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 1 | ????50 ? | ????72 ? | ????＜30 ? | ????＞10 ? | + ? |
The group practices of table 5 Carnitine Fumarate and mixed-matrix
(Carnitine Fumarate: mixed-matrix=1: 2)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 1 | ????33.3 ? | ????89 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 1 | ????33.3 ? | ????89 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 1 | ????33.3 ? | ????87 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 1 | ????33.3 ? | ????83 ? | ????＜30 ? | ????＞10 ? | ++ ? |
The group practices of table 6 Carnitine Fumarate and mixed-matrix
(Carnitine Fumarate: mixed-matrix=1: 5)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 1 | ????16.7 ? | ????88 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 1 | ????16.7 ? | ????87 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 1 | ????16.7 ? | ????86 ? | ????＜30 ? | ????＞10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 1 | ????16.7 ? | ????83 ? | ????＜30 ? | ????＞10 ? | +++ ? |
The group practices of table 7 Carnitine Fumarate and mixed-matrix
(Carnitine Fumarate: mixed-matrix=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 5 | ????50 ? | ????91 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 5 | ????50 ? | ????91 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 5 | ????50 ? | ????90 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 5 | ????50 ? | ????88 ? | ????＜30 ? | ????＜10 ? | ++ ? |
The group practices of table 8 Carnitine Fumarate and mixed-matrix
(Carnitine Fumarate: mixed-matrix=1: 2)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 5 | ????33.3 ? | ????93 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 5 | ????33.3 ? | ????93 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 5 | ????33.3 ? | ????92 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 5 | ????33.3 ? | ????89 ? | ????＜30 ? | ????＜10 ? | +++ ? |
The group practices of table 9 Carnitine Fumarate and mixed-matrix
(Carnitine Fumarate: mixed-matrix=1: 5)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 5 | ????16.7 ? | ????93 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 5 | ????16.7 ? | ????92 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 5 | ????16.7 ? | ????93 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 5 | ????16.7 ? | ????90 ? | ????＜30 ? | ????＜10 ? | +++ ? |
The group practices of table 10 Carnitine Fumarate and mixed-matrix
(Carnitine Fumarate: mixed-matrix=1: 1)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 10 | ????50 ? | ????92 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 10 | ????50 ? | ????91 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 10 | ????50 ? | ????88 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 10 | ????50 ? | ????84 ? | ????＜30 ? | ????＞10 ? | +++ ? |
The group practices of table 11 Carnitine Fumarate and mixed-matrix
(Carnitine Fumarate: mixed-matrix=1: 2)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 10 | ????33.3 ? | ????92 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 10 | ????33.3 ? | ????92 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 10 | ????33.3 ? | ????90 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 10 | ????33.3 ? | ????87 ? | ????＜30 ? | ????＜10 ? | +++ ? |
The group practices of table 12 Carnitine Fumarate and mixed-matrix
(Carnitine Fumarate: mixed-matrix=1: 5)
| The substrate title | Effective ingredient (%) | Rounding rate (%) | Dissolve scattered time limit (minute) | The ball method of double differences different (%) | Hardness |
| Polyoxyethylene stearate 40 esters: Polyethylene Glycol=1: 10 | ????16.7 ? | ????93 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Poloxamer: Polyethylene Glycol=1: 10 | ????16.7 ? | ????92 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Carboxymethyl starch sodium: Polyethylene Glycol=1: 10 | ????16.7 ? | ????90 ? | ????＜30 ? | ????＜10 ? | +++ ? |
| Betacyclodextrin: Polyethylene Glycol=1: 10 | ????16.7 ? | ????91 ? | ????＜30 ? | ????＜10 ? | +++ ? |
1. the result from above several groups of tables can see: when the ratio of L-carnitine and substrate was 1: 1, its rounding rate, the ball method of double differences was different and index such as hardness is all undesirable, and dissolve scattered time limit institute is influenced not obvious.
2. when the ratio of L-carnitine and substrate is 1: 2, the rounding rate, the ball method of double differences is different and index such as hardness slightly all begins to enter preferable state.
3. when the ratio of L-carnitine and substrate is 1: 5, the rounding rate, the ball method of double differences is different and index such as hardness improves not obvious.
4. the general effect of composite interstitial substance is better than single-matrix.
5. the hardness method for expressing in the subordinate list adopts drop pill is placed on the glass plate, press...withes one's finger it, observes its metamorphosis."+" expression flicking promptly is out of shape, " ++ " expression distortion of firmly pressing, and " +++" expression is indeformable by it.
Reference material:
1. flood is defended the country. the nutrition pharmacological action of L-carnitine. and the practical medical science 1998.3-1P.25-27 in Zhejiang;
2. Cao abides by hero, Yu Weidong. take the influence of U.S. of health to swimmer's body fat etc. and sports and scientific research 1996.12.17-4P.51-53.
Claims (8)
1. a levo carnitine dropping pill that is used for the treatment of obesity and hepatopathy is an active pharmaceutical ingredient with the L-carnitine, forms with the pharmaceutically suitable carrier as substrate, wherein L-carnitine is defined by following title: English name L-carnitine, Chinese translation is Kang Liting, calls to be levocarnitine, vitamin B
T, chemistry L-β-hydroxyl by name-γ-first ammonium butanoic acid, molecular formula C
7H
15NO
3, chemical structural formula.
2. levo carnitine dropping pill that is used for the treatment of obesity and hepatopathy, with the L-carnitine-L-tartrate is active pharmaceutical ingredient, form with the pharmaceutically suitable carrier as substrate, wherein the chemical name of L-carnitine-L-tartrate is: (R)-and two [(3-carboxyl-2-hydroxypropyl) is trimethylammonio]-L-tartrates.
3. levo carnitine dropping pill that is used for the treatment of obesity and hepatopathy, with the Carnitine Fumarate is active pharmaceutical ingredient, form with pharmaceutically suitable carrier as substrate, wherein the chemical name of Carnitine Fumarate is: (R)-and 3-carboxyl-2-hydroxy-n, N, the N-trimethyl third ammonium fumarate, or (R)-3 (3-carboxyl-2-hydroxypropyl) is trimethylammonio-fumarate.
4. as any levo carnitine dropping pill of claim 1 or claim 2 or claim 3, it is characterized in that: described substrate is Polyethylene Glycol
(2000～20000), polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac, the mixture of wherein one or more;
5. as any levo carnitine dropping pill of claim 1 or claim 2 or claim 3, it is characterized in that: described substrate is the mixture of polyoxyethylene stearate 40 esters and Polyethylene Glycol or poloxamer and Polyethylene Glycol or carboxymethyl starch sodium and Polyethylene Glycol or betacyclodextrin and Polyethylene Glycol; With g or kg is unit, and by weight, its mixed proportion is polyoxyethylene stearate 40 esters: Polyethylene Glycol or poloxamer: Polyethylene Glycol or carboxymethyl starch sodium: Polyethylene Glycol or betacyclodextrin: Polyethylene Glycol=1: 1～1: 10.
6. as any levo carnitine dropping pill of claim 1 or claim 2 or claim 3, it is characterized in that the ratio of described active pharmaceutical ingredient and described substrate is: with g or kg is unit, active pharmaceutical ingredient: substrate=1: 1～1: 5.
7. the preparation method of a levo carnitine dropping pill is made of following step:
7.1 active pharmaceutical ingredient---L-carnitine or L-carnitine-L-tartrate or Carnitine Fumarate;
7.2 substrate---Polyethylene Glycol
(2000～20000), polyoxyethylene stearate 40 esters, betacyclodextrin, poloxamer, carboxymethyl starch sodium, sodium lauryl sulphate, stearic acid, sodium stearate, glycerin gelatine, Lac, the mixture of wherein one or more;
7.3 proportioning: with g or kg is unit, L-carnitine or its esters: substrate=1: 1～1: 5;
7.4, accurately take by weighing each supplementary material according to the given ratio of prescription, be placed on heating while stirring in the heating container, standby until the fused solution that obtains containing active pharmaceutical ingredient and substrate and/or emulsion and/or suspension;
7.5 adjust the temperature control system of drop pill machine, make the water dropper temperature heating of drop pill machine and remain on 50 ℃～90 ℃, the temperature cooling of condensing agent also remains on 40 ℃～-5 ℃;
7.6 when treating that the temperature of condensing agent in dropping-pill machine head and the condensation column is stable respectively and reaching desired state of temperature, fused solution and/or the emulsion and/or the suspension that will contain active pharmaceutical ingredient and substrate, place in the water dropper jar of drop pill machine, splash in the condensing agent and shrink shaping promptly.
8. as the preparation method of levo carnitine dropping pill as described in the claim 7, it is characterized in that: condensing agent can be liquid paraffin or/and methyl-silicone oil or/and in the vegetable oil.
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| CN104739776A (en) * | 2015-04-15 | 2015-07-01 | 福州乾正药业有限公司 | Solid dispersion composition of levocarnitine as well as preparation method and medical application of solid dispersion composition |
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|---|---|---|---|---|
| DE2921852A1 (en) * | 1979-05-29 | 1980-12-11 | Fresenius Chem Pharm Ind | LIPID LOWERING AGENT |
| IT1272290B (en) * | 1994-06-20 | 1997-06-16 | Avantgarde Spa | SALT OF L-CARNITINE AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN IT FOR THE TREATMENT OF SKIN DISEASES |
| EP0972516A1 (en) * | 1998-06-25 | 2000-01-19 | SIGMA-TAU Industrie Farmaceutiche Riunite S.p.A. | Gastro-intestinal adverse effect-free composition comprising an L-carnitine replacement. |
| CN1513445A (en) * | 2003-05-16 | 2004-07-21 | 浙江天一堂集团有限公司 | Sodium bouttuynin small pellet, and its prepn. method |
| JP5024585B2 (en) * | 2005-11-07 | 2012-09-12 | 株式会社興人 | Novel itaconic sugar derivative and process for producing the same |
-
2005
- 2005-02-24 CN CNB2005100089035A patent/CN1322860C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104739776A (en) * | 2015-04-15 | 2015-07-01 | 福州乾正药业有限公司 | Solid dispersion composition of levocarnitine as well as preparation method and medical application of solid dispersion composition |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1322860C (en) | 2007-06-27 |
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