CN101269039A - Levorotation carnitine sustained-release dropping pill and preparation method thereof - Google Patents
Levorotation carnitine sustained-release dropping pill and preparation method thereof Download PDFInfo
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- CN101269039A CN101269039A CNA2008101118359A CN200810111835A CN101269039A CN 101269039 A CN101269039 A CN 101269039A CN A2008101118359 A CNA2008101118359 A CN A2008101118359A CN 200810111835 A CN200810111835 A CN 200810111835A CN 101269039 A CN101269039 A CN 101269039A
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Abstract
The invention relates to a drug for treating adiposis and hepatopatic diseases and particularly relates to a drug compound oral pharmaceutical formulation adopting L-carnitine (or L-carnitine salts) as drug active ingredient and having the effects of reducing weight and inhibiting hepatopatic diseases. The drug aims to supplement the deficiency of the prior art and provide a sustained-release L-carnitine dropping pill formulation. The sustained-release L-carnitine dropping pill is prepared by adding stabilize Vitamin E to the ingredients accepted in the prior art to guarantee no occurrence of an obvious change related to the substance content for the drug during the effective storage period and has the advantages of full release, controllable release time and high bioavailability simultaneously. The sustained-release L-carnitine dropping pill is suitable for clinical and family use.
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 medicine levorotation carnitine sustained-release oral formulations 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 the effect of playing promotion fatty acid beta oxidation in the film outside mitochondrial membrane.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.
Patient with obesity needs a long periods of treatment process, concerning the patient who heals with medicine, just need be a kind of rapid-action, and the time of proving effective is long, the medicine that medicining times is few.
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.
Summary of the invention
The objective of the invention is to replenish the deficiencies in the prior art, a kind of levorotation carnitine sustained-release dropping pill preparation is provided.Levorotation carnitine sustained-release dropping pill involved in the present invention, be in the component that adopts in prior art, added the stabilizing agent vitamin E, guarantee that the obvious change of its related substances can not take place medicine in effective storage period, it is abundant also to have simultaneously release, drug release time is controlled, the advantage that bioavailability is high, and suitable clinical and family uses.
Of the present invention and levo carnitine dropping pill be to be active constituents of medicine with L-carnitine or its esters, with hydrophilic framework material and hydrophobicity framework material as substrate, a kind of granular pattern drug oral preparation that forms through specific prepared.
Be prepared by the following technical solutions, can obtain levorotation carnitine sustained-release 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
TChemical 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
[preparation method]
1. component constitutes: calculate according to percentage by weight, levorotation carnitine sustained-release dropping pill involved in the present invention is made up of substrate and the 0.5-5% stabilizing agent of 10-40% L-carnitine and 60-90%, and substrate comprises 40-80% hydrophilic framework material and 10-30% hydrophobicity framework material.
2. in the said components, the hydrophilic framework material in the described substrate is made up of Polyethylene Glycol (PEG) 4000 or Polyethylene Glycol (PEG) 6000 or Polyethylene Glycol (PEG) 10000 or their mixture of polyoxyethylene stearate (40) ester (S-40).
3. in the said components, the hydrophobic framework material in the described substrate is made up of glyceryl monostearate or stearic acid or octadecanol or their mixture.
4. in the said components, described stabilizing agent is made up of vitamin E.
5. preparation method: take by weighing described hydrophilic framework material and hydrophobicity framework material earlier, place the heating container internal heating and stir and make it to dissolve, the L-carnitine that adds corresponding proportion, fully stir, add again after stabilizing agent stirs, under heat-retaining condition, the medicinal liquid of fusion or mixing is splashed in the condensation column that fills dimethicone, take out after being shaped, promptly.
6. in the above-mentioned preparation method, the temperature during described heating and melting is 55 ℃～85 ℃.
7. in the above-mentioned preparation method, described condensed fluid is the dimethicone greater than 150#.
8. in the above-mentioned preparation method, the temperature on described condensed fluid top is 20 ℃～30 ℃, and the temperature of bottom is-4 ℃～10 ℃.
Beneficial effect
Existing L-carnitine oral formulations all is tablet or capsule, is having a wide range of applications aspect treatment obesity, hepatopathy and the part cardiovascular diseases clinically.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.
The levorotation carnitine sustained-release dropping pill that reaches of the present invention, 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, the total surface area of medicine is increased.And substrate has the hydrophilic framework material; medicine had wetting action; can make medicine molten microgranule or the solution of loosing into rapidly; thereby make the dissolving of medicine and absorb quickening, thereby improved bioavailability, brought into play efficient, quick-acting effects; because of having the hydrophobicity framework material, substrate exists again; make the medicine release abundant, release is controlled, and medicining times waits effect less.After medicine has added stabilizing agent, make medicine more stable, in effective storage life, the change of related substance can not take place at medicine.
The specific embodiment
Now with several groups of specific embodiments, be described further with regard to the preparation method of levorotation carnitine sustained-release dropping pill of the present invention.
First group:
In gross weight 100g, take by weighing substrate PEG4000 40%, PEG6000 10%, and PEG10000 10%, stearic acid 11%, glyceryl monostearate 17%, stabilizing agent vitamin E 2%, raw material L-carnitine 10%; Substrate is made it to dissolve in placing the heating container internal heating and stirring, the L-carnitine that adds corresponding proportion, fully stir, add again after the stabilizing agent vitamin E stirs, under heat-retaining condition, the medicinal liquid of fusion or mixing is splashed in the condensation column that fills dimethicone, wherein, temperature during heating and melting is 55 ℃, and the temperature on condensed fluid top is 20 ℃, and the temperature of bottom is-4 ℃; The back taking-up is shaped.
Products obtained therefrom, 2 hours cumulative release percentage rate are that 35～55%, 6 hours cumulative release percentage rate are that 62～82%, 10 hours cumulative release percentage rate are 75～95%, continuous 3 months no significant change of related substance examination, roundness is better.
Second group:
In gross weight 100g, take by weighing substrate PEG4000 10%, PEG6000 20%, and PEG10000 30%, stearic acid 11%, glyceryl monostearate 8.5%, stabilizing agent vitamin E 0.5%, raw material L-carnitine 20%; Substrate is made it to dissolve in placing the heating container internal heating and stirring, the L-carnitine that adds corresponding proportion, fully stir, add again after the stabilizing agent vitamin E stirs, under heat-retaining condition, the medicinal liquid of fusion or mixing is splashed in the condensation column that fills dimethicone, wherein, temperature during heating and melting is 65 ℃, and the temperature on condensed fluid top is 30 ℃, and the temperature of bottom is 0 ℃; The back taking-up is shaped.
Products obtained therefrom, 2 hours cumulative release percentage rate are that 48%～68%, 6 hours cumulative release percentage rate are that 75～95%, 10 hours cumulative release percentage rate are 80～100%, continuous 3 months no significant change of related substance examination, roundness is better.
The 3rd group:
In gross weight 100g, take by weighing substrate polyoxyethylene stearate (40) ester (S-40) 10%, PEG6000 10%, and PEG10000 20%, stearic acid 10%, octadecanol 7%, stabilizing agent vitamin E 3%, raw material L-carnitine 40%; Substrate is made it to dissolve in placing the heating container internal heating and stirring, the L-carnitine that adds corresponding proportion, fully stir, add again after the stabilizing agent vitamin E stirs, under heat-retaining condition, the medicinal liquid of fusion or mixing is splashed in the condensation column that fills dimethicone, wherein, temperature during heating and melting is 75 ℃, and the temperature on condensed fluid top is 20 ℃, and the temperature of bottom is 0 ℃; The back taking-up is shaped.
Products obtained therefrom, 2 hours cumulative release percentage rate are that 35%～55%, 6 hours cumulative release percentage rate are that 60～80%, 10 hours cumulative release percentage rate are 70～90%, continuous 3 months no significant change of related substance examination, roundness is better.
The 4th group:
In gross weight 100g, take by weighing substrate polyoxyethylene stearate (40) ester (S-40) 10%, PEG6000 15%, and PEG10000 30%, glyceryl monostearate 2%, octadecanol 8%, stabilizing agent vitamin E 5%, raw material L-carnitine 30%; Substrate is made it to dissolve in placing the heating container internal heating and stirring, the L-carnitine that adds corresponding proportion, fully stir, add again after the stabilizing agent vitamin E stirs, under heat-retaining condition, the medicinal liquid of fusion or mixing is splashed in the condensation column that fills dimethicone, wherein, temperature during heating and melting is 85 ℃, and the temperature on condensed fluid top is 30 ℃, and the temperature of bottom is 5 ℃; The back taking-up is shaped.
Products obtained therefrom, 2h cumulative release percentage rate is 39%～59%, and 6h cumulative release percentage rate is 64～84%, and 10h cumulative release percentage rate is 76～96%,, continuous 3 months no significant change of related substance examination, roundness is better.
The 5th group:
In gross weight 100g, take by weighing substrate polyoxyethylene stearate (40) ester (S-40) 10%, PEG4000 10%, and PEG6000 30%, stearic acid 5%, glyceryl monostearate 3%, octadecanol 10%, stabilizing agent vitamin E 2%, raw material L-carnitine 30%; Substrate is made it to dissolve in placing the heating container internal heating and stirring, the L-carnitine that adds corresponding proportion, fully stir, add again after the stabilizing agent vitamin E stirs, under heat-retaining condition, the medicinal liquid of fusion or mixing is splashed in the condensation column that fills dimethicone, wherein, temperature during heating and melting is 65 ℃, and the temperature on condensed fluid top is 20 ℃, and the temperature of bottom is 4 ℃; The back taking-up is shaped.
Products obtained therefrom, 2h cumulative release percentage rate is 42%～62%, and 6h cumulative release percentage rate is 69～89%, and 10h cumulative release percentage rate is 76～96%, continuous 3 months no significant change of related substance examination, roundness is better.
The 6th group:
In gross weight 100g, take by weighing substrate polyoxyethylene stearate (40) ester (S-40) 10%, PEG4000 20%, and PEG6000 20%, PEG1000020%, stearic acid 11%, glyceryl monostearate 7%, stabilizing agent vitamin E 2%, raw material L-carnitine 10%; Substrate is made it to dissolve in placing the heating container internal heating and stirring, the L-carnitine that adds corresponding proportion, fully stir, add again after the stabilizing agent vitamin E stirs, under heat-retaining condition, the medicinal liquid of fusion or mixing is splashed in the condensation column that fills dimethicone, wherein, temperature during heating and melting is 70 ℃, and the temperature on condensed fluid top is 30 ℃, and the temperature of bottom is 0 ℃; The back taking-up is shaped.
Products obtained therefrom, 2h cumulative release percentage rate is 40%～60%, and 6h cumulative release percentage rate is 70～88%, and 10h cumulative release percentage rate is 80～95%, continuous 3 months no significant change of related substance examination, roundness is better.
Claims (5)
1. levorotation carnitine sustained-release dropping pill that is used for the treatment of obesity and hepatopathy and preparation method thereof, with the L-carnitine is active pharmaceutical ingredient, with being prepared from by certain component formation, wherein as the hydrophilic framework material of substrate and the pharmaceutically suitable carrier and the certain amount of stabilizer of hydrophobicity framework material:
1.1 described component constitutes: calculate according to percentage by weight, levorotation carnitine sustained-release dropping pill involved in the present invention is made up of substrate and the 0.5-5% stabilizing agent of 10-40% L-carnitine and 60-90%, and substrate comprises 40-80% hydrophilic framework material and 10-30% hydrophobicity framework material;
1.2 the hydrophilic framework material in the described substrate is made up of Polyethylene Glycol (PEG) 4000 or Polyethylene Glycol (PEG) 6000 or Polyethylene Glycol (PEG) 10000 or their mixture of polyoxyethylene stearate (40) ester (S-40);
1.3 the hydrophobic framework material in the described substrate is made up of glyceryl monostearate or stearic acid or octadecanol or their mixture;
1.4 described stabilizing agent is made up of vitamin E.
2. the described levorotation carnitine sustained-release dropping pill of claim 1, its preparation method is as follows:
Take by weighing described hydrophilic framework material and hydrophobicity framework material earlier, place the heating container internal heating and stir and make it to dissolve, the L-carnitine that adds corresponding proportion, fully stir, add again after stabilizing agent stirs, under heat-retaining condition, the medicinal liquid of fusion or mixing is splashed in the condensation column that fills dimethicone, take out after being shaped, promptly.
3. the described preparation method of claim 2, the temperature when it is characterized in that described heating and melting is 55 ℃～85 ℃.
4. the described preparation method of claim 2 is characterized in that described condensed fluid is the dimethicone greater than 150#.
5. the described preparation method of claim 2, the temperature that it is characterized in that described condensed fluid top is 20 ℃～30 ℃, the temperature of bottom is-4 ℃～10 ℃.
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| CNA2008101118359A CN101269039A (en) | 2008-05-16 | 2008-05-16 | Levorotation carnitine sustained-release dropping pill and preparation method thereof |
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| CNA2008101118359A CN101269039A (en) | 2008-05-16 | 2008-05-16 | Levorotation carnitine sustained-release dropping pill and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109820836A (en) * | 2019-03-22 | 2019-05-31 | 大连医诺生物股份有限公司 | Levorotation carnitine sustained-release microcapsule powder and preparation method thereof |
| CN111990574A (en) * | 2020-09-18 | 2020-11-27 | 内蒙古精晶生物科技有限公司 | L-carnitine nutritional effervescent tablet |
-
2008
- 2008-05-16 CN CNA2008101118359A patent/CN101269039A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109820836A (en) * | 2019-03-22 | 2019-05-31 | 大连医诺生物股份有限公司 | Levorotation carnitine sustained-release microcapsule powder and preparation method thereof |
| CN111990574A (en) * | 2020-09-18 | 2020-11-27 | 内蒙古精晶生物科技有限公司 | L-carnitine nutritional effervescent tablet |
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Open date: 20080924 |