CN1218690C - Liposome medicine enteric capsule preparation - Google Patents
Liposome medicine enteric capsule preparation Download PDFInfo
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- CN1218690C CN1218690C CN 02139428 CN02139428A CN1218690C CN 1218690 C CN1218690 C CN 1218690C CN 02139428 CN02139428 CN 02139428 CN 02139428 A CN02139428 A CN 02139428A CN 1218690 C CN1218690 C CN 1218690C
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Abstract
The present invention relates to a liposome medicine enteric capsule preparation suitable for clinic, which comprises the following components: a medicine with therapeutic action, phosphatide of a liposome coating material and a mucosa absorption penetration promoting agent, cholesterol of the liposome coating material, vitamin E of an antioxidant, a protective agent of liposome freeze drying, a diluting agent favorable to encapsulate the liposome medicine, a powder flow aid favorable to liposome medicine forming preferable flowability, and an enteric capsule for preventing the liposome medicine from decomposing and damaging by gastric juice. The liposome medicine enteric capsule preparation prepared by whole or part of the compounds adopts liposome medicine transmission technology and positioning medicine release technology of the enteric capsule. The water-solubility and the uniformity of difficultly soluble medicine are preferably solved by liposome wrapping. The present invention avoids the damage of the use of the traditional dissolving agent with side effect and gastric juice to medicine and the liposome medicine and the stimulation of the medicine to gastric mucosa, enhances the absorption of the medicine passing through intestinal mucosa and enhances blood medicine concentration and medicine effect.
Description
Technical field
The invention belongs to field of medicaments, relate to capsule preparations, particularly liposome medicament enteric coated capsule preparation.
Background technology
Liposome technology is a kind of advanced person's the medicine technology of passing, and liposome itself is very little to human toxicity, and human body is not had immunization.Liposome medicament makes medicine have the targeting feature of directional profile in vivo, and medicine is encapsulated in the liposome, can reduce the toxicity of medicine, increases curative effect.Liposomal pharmaceutical preparation can reduce the elimination speed of medicine, prolong drug action time, increases the inside and outside stability of medicine.Liposome has the biomembrane characteristic, can promote medicine from mucosa absorption after oral.
After simple liposome medicament was oral, under one's belt because the highly acid (pH1.0) of gastric juice and the Digestion of gastric enzyme, liposome will be destroyed and cause the medicine leakage, can not play the advantage function of liposome medicament.And the enteric hollow capsule of merely medicine being packed into, though avoided the toxic and side effects of medicine to stomach, avoided the destruction of gastric juice to medicine, but owing to lacked the liposome delivery system, medicine will be restricted in the absorption of intestinal, and can be very fast by metabolism after the drug absorption, and blood drug level peak valley ratio is big, the curative effect of medicine can be affected, and toxic and side effects is bigger.And medicine directly contacts with intestinal mucosa, can certain stimulation be arranged to intestinal mucosa.
And liposome medicament is packed in the enteric hollow capsule, both avoided the destruction of gastric juice to liposome medicament, avoided medicine to the zest of gastric mucosa and gastric juice destruction to medicine, avoided the zest of medicine again to intestinal mucosa, the biomembrane characteristic of liposome can promote the absorption of medicine, improve blood drug level, strengthen drug effect, liposome medicament also has targeting and long-acting, reduced the elimination speed of medicine, prolong the action time of medicine, reduced the peak valley ratio of blood drug level, reduced the toxic and side effects of medicine.
Below be the relevant references that the inventor retrieves:
[1]Hope，M.J.，Bally，M.B.，Webb，G.and Cullis，P.R.1985，Production oflarge unilamellar vesicles by a rapid extrusion procedure.Characterization of sizedistribution，trapped volume and ability to maintain a membrane potential，Biochim.Biophys.Acta.，812，55-65。
[2]A.Desjardins，Tao Chen，H.Khalil，K.Sayasith，J.Lagace，2002，Differential behaviour of fluid liposomes toward mammalian epithelial cells andbacteria：Restriction of fusion to bacteria，Journal of Drug Targeting，10(1)，47-54。
[3] Xi Nianzhu chief editor. pharmaceutics. Beijing people's health publishing house.
Summary of the invention
Liposome medicament enteric coated capsule preparation of the present invention, be intended to utilize advanced liposome to pass the positioning release medicine technology of medicine technology and enteric coated capsule, solve the water solublity and the homogeneity of fat-soluble and insoluble drug by liposome, strengthen the absorption of medicine by intestinal mucosa, improve blood drug level, strengthen drug effect, avoid the use of traditional cosolvent of side effect, enteric coated capsule does not discharge medicine in gastric juice, avoided the destruction of gastric juice, also reduced the zest of medicine gastric mucosa to medicine and liposome medicament.
To achieve these goals, the technical scheme of the present invention's solution is: liposome medicament enteric coated capsule preparation is characterized in that: this enteric coated capsule preparation includes the raw material of following weight ratio:
0.01～80.0% medicine, 5.0%～75.0% lecithin, 0.1%～5.0% cholesterol, 0～5.0% vitamin E, 5.0%～80.0% protective agent, 1.0%～70.0% diluent or filler, 0.01%～10.0% fluidizer, the total amount of raw material are 100%;
Above-mentioned said protective agent is wherein a kind of of mannitol, lactose, sodium chloride, gelatin hydrolysate, glucose;
Said medicine is a bezafibrate, cyclosporin, methotrexate, fluorouracil, mitomycin, cortisone, hydrocortisone, prednisone, methyltestosterone, danazol, norethindrone, megestrol, insulin, tolbutamide, glibenclamide, glipizide, gliclazide, vitamin A, vitamin D, vitamin B2, erythromycin, erythromycin ethylsuccinate, midecamycin, Acetylmidecamycin, Roxithromycin, clarithromycin, azithromycin, rokitamycin, sulfadiazine, silver sulfadiazine, Sulfamethoxazole, furazolidone, insulin, indomethacin, aspirin, wherein any of ibuprofen.
Promptly, liposome medicament enteric coated capsule of the present invention, including 1) weight ratio is 0.01～80.0% the medicine with therapeutical effect, 2) weight ratio is 5.0%～75.0% phospholipid, 3) weight ratio is 0.1%～5.0% cholesterol, 4) weight ratio is 0～5.0% vitamin E, 5) weight ratio is 5.0%～80.0% mannitol, 6) weight ratio is 1.0%～70.0% lactose, 7) weight ratio is 0.01%～10.0% micropowder silica gel and Pulvis Talci; The ratio of each component is based on the weight of liposomal body composition formula.Liposome medicament enteric coated capsule preparation be with drug encapsulation in the lipid bilayer of liposome, make the spherical drug-loaded liposome of superminiature
[1], moisture is removed in lyophilization then, adds suitable adjuvant again, is loaded in the enteric coated capsule promptly.
The similar cellularity of liposome, biomembranous characteristic and function are arranged, it can coated water-soluble and fat-soluble two types medicine, is a kind of multi-functional targeted drug carrier that has, and can reduce poisonous side effect of medicine, improves bioavailability and have the long-acting slow-release effect.
The not disintegrate under one's belt of liposome medicament enteric coated capsule
[2], just disintegrate and discharge medicine when emptying arrives small intestinal from stomach.Some medicine is subject to stomach acids destroy, and is unstable in gastric juice, as enzyme drug; Some medicine has very strong zest to gastric mucosa, causes the patient suffering easily or causes gastric mucosal lesion, as nonsteroidal antiinflammatory drug; Some patient's stomach has illness, can not absorb the drug; Some medicine does not absorb or absorption difference under sour environment, needs to absorb easily under alkaline environment.More than these drug encapsulation in liposome, reinstall enteric coated capsule, can avoid the generation of above-mentioned situation.
The specific embodiment
For a more clear understanding of the present invention, the present invention is described in further detail below in conjunction with embodiment that the inventor finishes according to technical scheme of the present invention, and the present invention is not limited to these embodiment.
4.1. medicine
Said medicine among the present invention is meant that the medicine with therapeutical effect comprises: (1) hypolipemic preparation, as bezafibrate; Immunosuppressant class medicine is as cyclosporin; Antitumor drug is as methotrexate, fluorouracil, mitomycin; Hormone medicine is as cortisone, hydrocortisone, prednisone, methyltestosterone, danazol, norethindrone, megestrol etc.; Diabetes class medicine such as insulin, tolbutamide, glibenclamide, glipizide, gliclazide; Vitamin medicaments vitamin A, D, B
2, E; Antibiotic erythromycin, erythromycin ethylsuccinate, midecamycin, Acetylmidecamycin, Roxithromycin, clarithromycin, azithromycin, rokitamycin in the macrolide; Synthetic antibiotic class medicine sulfadiazine, silver sulfadiazine, Sulfamethoxazole, furazolidone or insoluble drug or fat-soluble medicine;
(2) antibiotic erythromycin in the macrolide, polypeptide and class medicine insulin, enzyme drug bromelain enzyme or be subject to the medicine of stomach acids destroy;
(3) indomethacin, aspirin, ibuprofen or to gastric mucosa medicine excitatory;
4.2. phospholipid as liposome coating material, mucosal absorption permeation accelerator
Said phospholipid as liposome coating material, mucosal absorption permeation accelerator among the present invention is so long as phospholipid and be that acceptable any phospholipid that can form liposome all can use in the pharmaceutics.Such phospholipid for example has natural phospholipid, chemosynthesis phospholipid or semi-synthetic phospholipid etc.Concrete example includes: Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline, synthetic lecithin, sphingomyelins, cephalin etc., can be singly with a kind of, also can be several share, its consumption accounts for the weight ratio of liposome medicament enteric coated capsule prescription, is typically about 5～75%.
4.3. as cholesterol of liposome coating material
Said cholesterol among the present invention, the effect in the liposome prescription are the rigidity that increases liposome, and its consumption accounts for the weight ratio of liposome medicament enteric coated capsule prescription, is typically about 0.1%～5.0%.
4.4. vitamin E as antioxidant
Said vitamin E among the present invention, the effect in the liposome prescription are that protection phospholipid is not oxidized, and its consumption accounts for the weight ratio of liposome medicament enteric coated capsule prescription, is typically about 0.001～5%.
4.5. the cryodesiccated protective agent of liposome
The cryodesiccated protective agent of said liposome among the present invention all can be accepted so long as play the chemical compound of proppant or auxiliary shape agent or filler in the cryodesiccated prescription of pharmaceutics.Concrete example includes: mannitol, lactose, sodium chloride, gelatin hydrolysate, glucose etc., its consumption generally accounts for 5%～85% of liposome medicament enteric coated capsule formulation weight.
4.6. diluent
Said diluent among the present invention, so long as diluent or filler commonly used all can be accepted in the pharmaceutics, concrete example includes starch, pregelatinized Starch, dextrin, Icing Sugar, lactose, glucose, mannitol, microcrystalline Cellulose, calcium sulfate, kaolin, calcium carbonate, light magnesium oxide, aluminium hydroxide, kollidon, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, alginate etc., lactose preferably, pregelatinized Starch, mannitol, microcrystalline Cellulose etc., can be single with a kind of, also can be several share, its consumption be generally 1%～70% of prescription weight.
4.7. fluidizer
Said fluidizer among the present invention, so long as fluidizer commonly used all can be accepted in the pharmaceutics, concrete example includes: micropowder silica gel, Pulvis Talci, stearate, calcium stearate, magnesium stearate, hydrogenated vegetable oil, Polyethylene Glycol, sodium lauryl sulphate, Stepanol MG etc., preferably micropowder silica gel, Pulvis Talci, magnesium stearate, can be single with a kind of, also can be several share, its consumption be generally 0.01%～5% of prescription weight.
4.8. enteric hollow capsule
Said enteric hollow capsule among the present invention can be that " enteric hollow capsule that records in the Chinese pharmacopoeia or do not recorded a kind of, model is unrestricted.
4.9 preparation method:
Phospholipid and cholesterol are dissolved in the adequate amount of ethanol, with medicine dissolution in suitable organic solvent, with two kinds of solution mixings, under the state of cutter high-speed stirred, mixed solution is joined in the 150ml water for injection slowly, promptly get the multiphasic liposomes drug solution.This liposome medicament solution is removed organic solvent with the ultrafilter ultrafiltration repeatedly, and make to replenish liquid with 0.9% sodium chloride solution, the volume of final ultrafiltrate is 100ml.Ultrafiltrate is pushed repeatedly through the film of squeezer with 200nm, obtain the large unilamellar vesicle drug solution of particle diameter 250 ± 40nm.Protective agent joined in the liposome medicament solution to stir make dissolving, divide to be filled in the 7ml cillin bottle every dress 5ml, lyophilization then; remove moisture, content is collected, add diluent, fluidizer; stir evenly, the enteric hollow capsule of packing into promptly makes liposome medicament enteric coated capsule preparation.
The present invention verifies the amount ranges of listed medicine in prescription.Under technical scheme of the present invention and process conditions, when liposome prescription except the lecithin consumption according to amount of drug the corresponding adjustment, other components and consumption are maintained fixed constant, and the arbitrary consumption of amount of drug in 0.01%～30.00% content range all guarantees to make stable final products.Though content of medicines can made the stabilized liposomes medicine below 0.01% in principle, its drug level does not reach valid density, has not had medicinal meaning, so do not investigated in an embodiment.
4.10 specific embodiment
4.10.1 (one) drug dose scope embodiment
4.10.1.1 insoluble drug or liposoluble medicinal liposome enteric coated capsule
The preparation of embodiment 1:0.02% (g/g) gliclazide liposome enteric-coated capsule
Prescription:
| Title | Weight (%) | Inventory (g) |
| Lecithin | 36.25 | 19.0 |
| Cholesterol | 1.91 | 1.0 |
| Gliclazide | 0.02 | 0.008 |
| Mannitol | 38.16 | 20 |
| Lactose | 19.08 | 10 |
| Micropowder silica gel | 3.82 | 2 |
| Magnesium stearate | 0.76 | 0.4 |
| Add up to | 100 | 52.408 |
Method for making: recipe quantity lecithin and cholesterol are dissolved in the 20ml ethanol, on magnetic stirrer, are heated to 45 ℃ while stirring, make it to dissolve fully, cool; Gliclazide is dissolved in the solution of making 50mg/ml in the chloroform; with above-mentioned two kinds of solution mixings; under the state of cutter high-speed stirred (3000r/min), mixed solution is joined in the 150ml water for injection slowly then; under the condition of nitrogen protection, continue to stir 30min, promptly get the multiphasic liposomes drug solution.This liposome medicament solution is removed organic solvent with the ultrafilter ultrafiltration repeatedly, and make to replenish liquid with 0.9% sodium chloride solution, the volume of final ultrafiltrate is 100ml.Ultrafiltrate is pushed repeatedly through the film of squeezer with 5 layers of 200nm, obtain the large unilamellar vesicle drug solution of particle diameter 250 ± 40nm.Mannitol joined in the liposome medicament solution to stir make dissolving, divide to be filled in the 7ml cillin bottle every dress 5ml, lyophilization then, remove moisture, content is collected, add lactose, micropowder silica gel and magnesium stearate, stir evenly, the enteric hollow capsule of packing into, promptly.
The preparation of embodiment 2:6.76% (g/g) gliclazide liposome enteric-coated capsule
Prescription:
| Title | Weight ratio (%) | Inventory (g) |
| Lecithin | 33.81 | 19.0 |
| Cholesterol | 1.78 | 1.0 |
| Gliclazide | 6.76 | 3.8 |
| Mannitol | 35.59 | 20 |
| Lactose | 17.79 | 10 |
| Micropowder silica gel | 3.56 | 2 |
| Magnesium stearate | 0.71 | 0.4 |
| Add up to | 100 | 56.2 |
Method for making: recipe quantity lecithin and cholesterol are dissolved in the 20ml ethanol, on magnetic stirrer, are heated to 45 ℃ while stirring, make it to dissolve fully, cool; Gliclazide is dissolved in the solution of making 50mg/ml in the chloroform; with above-mentioned two kinds of solution mixings; under the state of cutter high-speed stirred (3000r/min), mixed solution is joined in the 150ml water for injection slowly then; under the condition of nitrogen protection, continue to stir 30min, promptly get the multiphasic liposomes drug solution.This liposome medicament solution is removed organic solvent with the ultrafilter ultrafiltration repeatedly, and make to replenish liquid with 0.9% sodium chloride solution, the volume of final ultrafiltrate is 100ml.Ultrafiltrate is pushed repeatedly through the film of squeezer with 5 layers of 200nm, obtain the large unilamellar vesicle drug solution of particle diameter 250 ± 40nm.Mannitol joined in the liposome medicament solution to stir make dissolving, divide to be filled in the 7ml cillin bottle every dress 5ml, lyophilization then, remove moisture, content is collected, add lactose, micropowder silica gel and magnesium stearate, stir evenly, the enteric hollow capsule of packing into, promptly.
4.10.1.2 be subject to the medicinal liposome enteric coated capsule of stomach acids destroy
The preparation of embodiment 3:0.02% (g/g) erythromycin liposome enteric-coated capsule
Prescription:
| Title | Weight ratio (%) | Inventory (g) |
| Lecithin | 36.25 | 19.0 |
| Cholesterol | 1.91 | 1.0 |
| Erythromycin | 0.02 | 0.01 |
| Mannitol | 38.16 | 20 |
| Lactose | 19.08 | 10 |
| Micropowder silica gel | 3.82 | 2 |
| Magnesium stearate | 0.76 | 0.4 |
| Add up to | 100 | 52.41 |
Method for making: recipe quantity lecithin, cholesterol, erythromycin are dissolved in the 20ml ethanol, on magnetic stirrer, are heated to 45 ℃ while stirring, make it to dissolve fully, cool; Under the state of cutter high-speed stirred (3000r/min), mixed solution is joined in the 150ml water for injection lentamente then, under the condition of nitrogen protection, continue to stir 30min, promptly get the multiphasic liposomes drug solution.This liposome medicament solution is removed organic solvent with the ultrafilter ultrafiltration repeatedly, and make to replenish liquid with 0.9% sodium chloride solution, the volume of final ultrafiltrate is 100ml.Ultrafiltrate is pushed repeatedly through the film of squeezer with 5 layers of 200nm, obtain the single-phase liposome medicament solution of big single chamber of particle diameter 250 ± 40nm.Mannitol joined in the liposome medicament solution to stir make dissolving, divide to be filled in the 7ml cillin bottle every dress 5ml, lyophilization then, remove moisture, content is collected, add lactose, micropowder silica gel and magnesium stearate, stir evenly, the enteric coated capsule of packing into No. 0, promptly.
The preparation of embodiment 4:0.02% (g/g) erythromycin liposome enteric-coated capsule
Prescription:
| Title | Weight ratio (%) | Inventory (g) |
| Lecithin | 31.12 | 19.0 |
| Cholesterol | 1.64 | 1.0 |
| Erythromycin | 14.16 | 8.65 |
| Mannitol | 32.76 | 20 |
| Lactose | 16.38 | 10 |
| Micropowder silica gel | 3.28 | 2 |
| Magnesium stearate | 0.66 | 0.4 |
| Add up to | 100 | 61.05 |
Method for making: recipe quantity lecithin, cholesterol, erythromycin are dissolved in the 20ml ethanol, on magnetic stirrer, are heated to 45 ℃ while stirring, make it to dissolve fully, cool; Under the state of cutter high-speed stirred (3000r/min), mixed solution is joined in the 150ml water for injection lentamente then, under the condition of nitrogen protection, continue to stir 30min, promptly get the multiphasic liposomes drug solution.This liposome medicament solution is removed organic solvent with the ultrafilter ultrafiltration repeatedly, and make to replenish liquid with 0.9% sodium chloride solution, the volume of final ultrafiltrate is 100ml.Ultrafiltrate is pushed repeatedly through the film of squeezer with 5 layers of 200nm, obtain the single-phase liposome medicament solution of big single chamber of particle diameter 250 ± 40nm.Mannitol joined in the liposome medicament solution to stir make dissolving, divide to be filled in the 7ml cillin bottle every dress 5ml, lyophilization then, remove moisture, content is collected, add lactose, micropowder silica gel and magnesium stearate, stir evenly, the enteric hollow capsule of packing into, promptly.
4.10.1.3 to stomach medicinal liposome enteric coated capsule excitatory
The preparation of embodiment 5:0.01% (g/g) indomethacin liposome enteric-coated capsule
Prescription:
| Title | Weight ratio (%) | Inventory (g) |
| Lecithin | 36.26 | 19.0 |
| Cholesterol | 1.91 | 1.0 |
| Indomethacin | 0.01 | 0.005 |
| Mannitol | 38.16 | 20 |
| Lactose | 19.08 | 10 |
| Micropowder silica gel | 3.82 | 2 |
| Magnesium stearate | 0.76 | 0.4 |
| Add up to | 100 | 52.405 |
Method for making: recipe quantity lecithin and cholesterol are dissolved in the 20ml ethanol, on magnetic stirrer, are heated to 45 ℃ while stirring, make it to dissolve fully, cool; Indomethacin is dissolved in the solution of making 50mg/ml in the acetone; with above-mentioned two kinds of solution mixings; under with the state of cutter high-speed stirred (3000r/min), mixed solution is joined in the 150ml water for injection lentamente then; under the condition of nitrogen protection, continue to stir 30min, promptly get the multiphasic liposomes drug solution.This liposome medicament solution is removed organic solvent with the ultrafilter ultrafiltration repeatedly, and make to replenish liquid with 0.9% sodium chloride solution, the volume of final ultrafiltrate is 100ml.Ultrafiltrate is pushed repeatedly through the film of squeezer with 5 layers of 200nm, obtain the single-phase liposome medicament solution of big single chamber of particle diameter 250 ± 40nm.Mannitol joined in the liposome medicament solution to stir make dissolving, divide to be filled in the 7ml cillin bottle every dress 5ml, lyophilization then, remove moisture, content is collected, add lactose, micropowder silica gel and magnesium stearate, stir evenly, the enteric hollow capsule of packing into, promptly.
The preparation of embodiment 6:7.45% (g/g) indomethacin liposome enteric-coated capsule
Prescription:
| Title | Weight ratio (%) | Inventory (g) |
| Lecithin | 33.56 | 19.0 |
| Cholesterol | 1.77 | 1.0 |
| Indomethacin | 7.45 | 4.22 |
| Mannitol | 35.32 | 20 |
| Lactose | 17.66 | 10 |
| Micropowder silica gel | 3.53 | 2 |
| Magnesium stearate | 0.71 | 0.4 |
| Add up to | 100 | 56.62 |
Method for making: recipe quantity lecithin, cholesterol are dissolved in the 20ml ethanol, on magnetic stirrer, are heated to 45 ℃ while stirring, make it to dissolve fully, cool; Indomethacin is dissolved in the solution of making 50mg/ml in the acetone, with above-mentioned two kinds of solution mixings; Under the state of cutter high-speed stirred (3000r/min), mixed solution is joined in the 150ml water for injection lentamente then, under the condition of nitrogen protection, continue to stir 30min, promptly get the multiphasic liposomes drug solution.This liposome medicament solution is removed organic solvent with the ultrafilter ultrafiltration repeatedly, and make to replenish liquid with 0.9% sodium chloride solution, the volume of final ultrafiltrate is 100ml.Ultrafiltrate is pushed repeatedly through the film of squeezer with 5 layers of 200nm, obtain the single-phase liposome medicament solution of big single chamber of particle diameter 250 ± 40nm.Mannitol joined in the liposome medicament solution to stir make dissolving, divide to be filled in the 7ml cillin bottle every dress 5ml, lyophilization then, remove moisture, content is collected, add lactose, micropowder silica gel and magnesium stearate, stir evenly, the enteric hollow capsule of packing into, promptly.
4.10.2 (two) each packaging material prescription amount ranges of medicinal liposome
The present invention verifies the amount ranges of listed liposome coating material.Under technical scheme of the present invention and process conditions, keeping medicine fat ratio is that 0.44: 1 (weight ratio) is constant, adjusts the ratio of phospholipid and cholesterol, and the arbitrary consumption in 99: 1～90: 10 (mol ratio) scopes can be made stable final products.
Embodiment 7: phospholipid and cholesterol mol ratio are the preparation of 99: 1 o'clock erythromycin liposome enteric-coated capsule
Prescription:
| Title | The lipid mol ratio | Weight ratio (%) | Inventory (g) |
| Lecithin | 99 | 32.11 | 19.46 |
| Cholesterol | 1 | 0.16 | 0.1 |
| Erythromycin | 14.27 | 8.65 | |
| Mannitol | 33.00 | 20 | |
| Lactose | 16.50 | 10 | |
| Micropowder silica gel | 3.30 | 2 | |
| Magnesium stearate | 0.66 | 0.4 | |
| Add up to | 100 | 60.61 |
Method for making: recipe quantity lecithin, cholesterol, erythromycin are dissolved in the 20ml ethanol, on magnetic stirrer, are heated to 45 ℃ while stirring, make it to dissolve fully, cool; Under the state of cutter high-speed stirred (3000r/min), mixed solution is joined in the 150ml water for injection lentamente then, under the condition of nitrogen protection, continue to stir 30min, promptly get the multiphasic liposomes drug solution.This liposome medicament solution is removed organic solvent with the ultrafilter ultrafiltration repeatedly, and make to replenish liquid with 0.9% sodium chloride solution, the volume of final ultrafiltrate is 100ml.Ultrafiltrate is pushed repeatedly through the film of squeezer with 5 layers of 200nm, obtain the single-phase liposome medicament solution of big single chamber of particle diameter 250 ± 40nm.Mannitol joined in the liposome medicament solution to stir make dissolving, divide to be filled in the 7ml cillin bottle every dress 5ml, lyophilization then, remove moisture, content is collected, add lactose, micropowder silica gel and magnesium stearate, stir evenly, the enteric hollow capsule of packing into, promptly.
Embodiment 8: phospholipid and cholesterol mol ratio are the preparation of 95: 5 o'clock erythromycin liposome enteric-coated capsule
Prescription:
| Title | The lipid mol ratio | Weight ratio (%) | Inventory (g) |
| Lecithin | 95 | 31.12 | 18.67 |
| Cholesterol | 5 | 0.83 | 0.5 |
| Erythromycin | 14.05 | 8.43 | |
| Mannitol | 33.33 | 20 | |
| Lactose | 16.67 | 10 | |
| Micropowder silica gel | 3.33 | 2 | |
| Magnesium stearate | 0.67 | 0.4 | |
| Add up to | 100 | 60.00 |
Method for making: recipe quantity lecithin, cholesterol, erythromycin are dissolved in the 20ml ethanol, on magnetic stirrer, are heated to 45 ℃ while stirring, make it to dissolve fully, cool; Under the state of cutter high-speed stirred (3000r/min), mixed solution is joined in the 150ml water for injection lentamente then, under the condition of nitrogen protection, continue to stir 30min, promptly get the multiphasic liposomes drug solution.This liposome medicament solution is removed organic solvent with the ultrafilter ultrafiltration repeatedly, and make to replenish liquid with 0.9% sodium chloride solution, the volume of final ultrafiltrate is 100ml.Ultrafiltrate is pushed repeatedly through the film of squeezer with 5 layers of 200nm, obtain the single-phase liposome medicament solution of big single chamber of particle diameter 250 ± 40nm.Mannitol joined in the liposome medicament solution to stir make dissolving, divide to be filled in the 7ml cillin bottle every dress 5ml, lyophilization then, remove moisture, content is collected, add lactose, micropowder silica gel and magnesium stearate, stir evenly, the enteric hollow capsule of packing into, promptly.
Embodiment 9: phospholipid and cholesterol mol ratio are the preparation of 90: 10 o'clock erythromycin liposome enteric-coated capsule
Prescription:
| Title | The lipid mol ratio | Weight ratio (%) | Inventory (g) |
| Lecithin | 90 | 29.83 | 17.69 |
| Cholesterol | 10 | 1.69 | 1.0 |
| Erythromycin | 13.86 | 8.22 | |
| Mannitol | 33.72 | 20 | |
| Lactose | 16.86 | 10 | |
| Micropowder silica gel | 3.37 | 2 | |
| Magnesium stearate | 0.67 | 0.4 | |
| Add up to | 100 | 59.31 |
Method for making: recipe quantity lecithin, cholesterol, erythromycin are dissolved in the 20ml ethanol, on magnetic stirrer, are heated to 45 ℃ while stirring, make it to dissolve fully, cool; Under the state of cutter high-speed stirred (3000r/min), mixed solution is joined in the 150ml water for injection lentamente then, under the condition of nitrogen protection, continue to stir 30min, promptly get the multiphasic liposomes drug solution.This liposome medicament solution is removed organic solvent with the ultrafilter ultrafiltration repeatedly, and make to replenish liquid with 0.9% sodium chloride solution, the volume of final ultrafiltrate is 100ml.Ultrafiltrate is pushed repeatedly through the film of squeezer with 5 layers of 200nm, obtain the single-phase liposome medicament solution of big single chamber of particle diameter 250nm ± 40nm.Mannitol joined in the liposome medicament solution to stir make dissolving, divide to be filled in the 7ml cillin bottle every dress 5ml, lyophilization then, remove moisture, content is collected, add lactose, micropowder silica gel and magnesium stearate, stir evenly, the enteric hollow capsule of packing into, promptly.
4.10.3 (three) vitamin E amount ranges embodiment
Embodiment 10: the vitamin E consumption is the preparation of the erythromycin liposome enteric-coated capsule of 1.00% (w/w)
Prescription:
| Title | The lipid mol ratio | Weight ratio (%) | Inventory (g) |
| Lecithin | 90 | 29.53 | 17.69 |
| Cholesterol | 10 | 1.67 | 1.0 |
| Vitamin E | 1.00 | 0.6 | |
| Erythromycin | 13.72 | 8.22 | |
| Mannitol | 33.38 | 20 | |
| Lactose | 16.69 | 10 | |
| Micropowder silica gel | 3.34 | 2 | |
| Magnesium stearate | 0.67 | 0.4 | |
| Add up to | 100 | 59.91 |
Method for making: recipe quantity lecithin, cholesterol, vitamin, erythromycin are dissolved in the 20ml ethanol, on magnetic stirrer, are heated to 45 ℃ while stirring, make it to dissolve fully, cool; Under the state of cutter high-speed stirred (3000r/min), mixed solution is joined in the 150ml water for injection lentamente then, under the condition of nitrogen protection, continue to stir 30min, promptly get the multiphasic liposomes drug solution.This liposome medicament solution is removed organic solvent with the ultrafilter ultrafiltration repeatedly, and make to replenish liquid with 0.9% sodium chloride solution, the volume of final ultrafiltrate is 100ml.Ultrafiltrate is pushed repeatedly through the film of squeezer with 5 layers of 200nm, obtain the single-phase liposome medicament solution of big single chamber of particle diameter 250 ± 40nm.Mannitol joined in the liposome medicament solution to stir make dissolving, divide to be filled in the 7ml cillin bottle every dress 5ml, lyophilization then, remove moisture, content is collected, add lactose, micropowder silica gel and magnesium stearate, stir evenly, the enteric hollow capsule of packing into, promptly.
Embodiment 11: the vitamin E consumption is the preparation of the erythromycin liposome enteric-coated capsule of 4.97% (w/w)
Prescription:
| Title | The lipid mol ratio | Weight ratio (%) | Inventory (g) |
| Lecithin | 90 | 28.34 | 17.69 |
| Cholesterol | 10 | 1.60 | 1.0 |
| Vitamin E | 4.97 | 3.1 |
| Erythromycin | 13.17 | 8.22 | |
| Mannitol | 32.05 | 20 | |
| Lactose | 16.02 | 10 | |
| Micropowder silica gel | 3.21 | 2 | |
| Magnesium stearate | 0.64 | 0.4 | |
| Add up to | 100 | 62.41 |
Method for making: recipe quantity lecithin, cholesterol, vitamin E, erythromycin are dissolved in the 20ml ethanol, on magnetic stirrer, are heated to 45 ℃ while stirring, make it to dissolve fully, cool; Under the state of cutter high-speed stirred (3000r/min), mixed solution is joined in the 150ml water for injection lentamente then, under the condition of nitrogen protection, continue to stir 30min, promptly get the multiphasic liposomes drug solution.This liposome medicament solution is removed organic solvent with the ultrafilter ultrafiltration repeatedly, and make to replenish liquid with 0.9% sodium chloride solution, the volume of final ultrafiltrate is 100ml.Ultrafiltrate is pushed repeatedly through the film of squeezer with 5 layers of 200nm, obtain the single-phase liposome medicament solution of big single chamber of particle diameter 250 ± 40nm.Mannitol joined in the liposome medicament solution to stir make dissolving, divide to be filled in the 7ml cillin bottle every dress 5ml, lyophilization then, remove moisture, content is collected, add lactose, micropowder silica gel and magnesium stearate, stir evenly, the enteric hollow capsule of packing into, promptly.
In sum, the present invention combines the positioning release medicine technology that liposome is passed medicine technology and capsulae enterosolubilis, has following five large advantages: (1) the present invention can be encapsulated in the cosolvent of having avoided use that side effect is arranged in the liposome duplicature with slightly solubility and fat-soluble medicine; (2) drug encapsulation can increase absorption, the enhancing drug effect of medicine in liposome; (3) liposome has slow releasing function, action time that can prolong drug; (4) the liposome medicament capsulae enterosolubilis of packing into can be positioned at small intestine and discharges medicine, has avoided gastric juice to the destruction of liposome medicament and medicine excitant and the toxicity to gastric mucosa; (5) medicine that for stomach the patient of illness is arranged or be difficult for absorbing at stomach can well be absorbed at small intestine. Therefore, the present invention has possessed novelty, creativeness and the practicality of Patent Law defined.
Claims (4)
1. liposome medicament enteric coated capsule preparation in the lipid bilayer of liposome, is made the spherical drug-loaded liposome of superminiature with drug encapsulation, and moisture is removed in lyophilization then, adds adjuvant again and is loaded in the enteric coated capsule; It is characterized in that: this enteric coated capsule preparation includes the raw material of following weight ratio:
0.01～80.0% medicine, 5.0%～75.0% lecithin, 0.1%～5.0% cholesterol, 0～5.0% vitamin E, 5.0%～80.0% protective agent, 1.0%～70.0% diluent or filler, 0.01%～10.0% fluidizer, the total amount of raw material are 100%;
Above-mentioned said protective agent is wherein a kind of of mannitol, lactose, sodium chloride, gelatin hydrolysate, glucose;
Said medicine is bezafibrate, cyclosporin, methotrexate, fluorouracil, mitomycin, cortisone, hydrocortisone, prednisone, methyltestosterone, danazol, norethindrone, megestrol, insulin, tolbutamide, glibenclamide, glipizide, gliclazide, vitamin A, vitamin D, vitamin B
2, wherein any of erythromycin, erythromycin ethylsuccinate, midecamycin, Acetylmidecamycin, Roxithromycin, clarithromycin, azithromycin, rokitamycin, sulfadiazine, silver sulfadiazine, Sulfamethoxazole, furazolidone, insulin, indomethacin, aspirin, ibuprofen.
2. according to the liposome medicament enteric coated capsule preparation of claim described 1, wherein said lecithin is: any in Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline, synthetic lecithin, the sphingomyelins or several.
3. by the described liposome medicament enteric coated capsule of claim 1 preparation, wherein said diluent comprises the one or more combination of starch, pregelatinized Starch, dextrin, Icing Sugar, lactose, glucose, mannitol, microcrystalline Cellulose, calcium sulfate, kaolin, calcium carbonate, light magnesium oxide, aluminium hydroxide, kollidon, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, alginate.
4. by the described liposome medicament enteric coated capsule of claim 1 preparation, wherein said fluidizer comprises the one or more combination of micropowder silica gel, Pulvis Talci, stearate, calcium stearate, magnesium stearate, hydrogenated vegetable oil, Polyethylene Glycol, sodium lauryl sulphate, Stepanol MG.
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| CN 02139428 CN1218690C (en) | 2002-09-17 | 2002-09-17 | Liposome medicine enteric capsule preparation |
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| CN 02139428 CN1218690C (en) | 2002-09-17 | 2002-09-17 | Liposome medicine enteric capsule preparation |
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| CN1218690C true CN1218690C (en) | 2005-09-14 |
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| CN101601652B (en) * | 2008-06-11 | 2012-07-04 | 天津金耀集团有限公司 | Momestasone furoate lipidosome cream |
| CN101816781A (en) * | 2010-04-22 | 2010-09-01 | 江西宇骏生物工程有限公司 | Gene recombinant human Cu-Zn superoxide dismutase liposome enteric-coated capsule and preparation method thereof |
| ES2909487T3 (en) * | 2017-03-30 | 2022-05-06 | Univ Heidelberg | Liposomal compositions and solid oral dosage forms comprising the same |
| CN106913557A (en) * | 2017-04-27 | 2017-07-04 | 武汉真福医药股份有限公司 | A kind of capsulae enterosolubilis and its preparation technology based on recombination bacillus subtilis fibrinolysin |
| TW202143978A (en) * | 2020-03-20 | 2021-12-01 | 大陸商江蘇恒瑞醫藥股份有限公司 | Glyburide liposome composition and preparation method thereof |
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