CN1857281A - Adefovir dipivoxil liposome injection and its preparing method - Google Patents
Adefovir dipivoxil liposome injection and its preparing method Download PDFInfo
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- CN1857281A CN1857281A CN 200510068334 CN200510068334A CN1857281A CN 1857281 A CN1857281 A CN 1857281A CN 200510068334 CN200510068334 CN 200510068334 CN 200510068334 A CN200510068334 A CN 200510068334A CN 1857281 A CN1857281 A CN 1857281A
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- liposome
- preparation
- adefovir
- injection
- lipid
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- 239000002502 liposome Substances 0.000 title claims abstract description 100
- 229960003205 adefovir dipivoxil Drugs 0.000 title claims abstract description 74
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 title claims abstract description 73
- 238000002347 injection Methods 0.000 title claims abstract description 42
- 239000007924 injection Substances 0.000 title claims abstract description 42
- 238000000034 method Methods 0.000 title claims description 26
- 238000002360 preparation method Methods 0.000 claims abstract description 81
- -1 adefovir ester Chemical class 0.000 claims description 77
- 229960001997 adefovir Drugs 0.000 claims description 76
- 150000002632 lipids Chemical class 0.000 claims description 53
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 22
- 239000000843 powder Substances 0.000 claims description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 18
- 235000012000 cholesterol Nutrition 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 16
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 9
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- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 7
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 6
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 6
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 6
- 229930195725 Mannitol Natural products 0.000 claims description 6
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 6
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 6
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- 239000002736 nonionic surfactant Substances 0.000 claims description 6
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- 238000004108 freeze drying Methods 0.000 claims description 5
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 4
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- 238000010438 heat treatment Methods 0.000 claims description 4
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- 238000002844 melting Methods 0.000 claims description 4
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- 229940107161 cholesterol Drugs 0.000 description 15
- 239000008215 water for injection Substances 0.000 description 15
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
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- 229960001627 lamivudine Drugs 0.000 description 3
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 3
- 230000007694 nephrotoxicity Effects 0.000 description 3
- 241000700721 Hepatitis B virus Species 0.000 description 2
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- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 description 1
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- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 1
- 229950006790 adenosine phosphate Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- CCHNOBQMQBSRHQ-UHFFFAOYSA-N phosphoric acid;7h-purin-6-amine Chemical compound OP(O)(O)=O.NC1=NC=NC2=C1NC=N2 CCHNOBQMQBSRHQ-UHFFFAOYSA-N 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The present invention relates to adefovir dipivoxil liposome injection and its preparation process. The adefovir dipivoxil liposome injection contains adefovir dipivoxil in 0.01-1 wt%, lipoid for preparing liposome in 0.05-15 wt% and/or pharmaceutically acceptable carrier.
Description
Technical field
The present invention relates to pharmaceutical preparation, particularly contain liposome ejection preparation of adefovir ester and preparation method thereof.
Background technology
Adefovir ester (Adefovir Dipivoxil) is the prodrug of adenine phosphate compound adefovirdipivoxil, is converted into adefovirdipivoxil through hydrolysis in vivo.Adefovirdipivoxil is the nucleotide of single adenosine phosphate and natural substrate deoxyadenine triphosphoric acid competition hepatitis b virus dna polymerase, enter the viral DNA chain after, cause that its DNA chain is synthetic to be ended, thereby hinder virus replication, have the broad-spectrum disease resistance cytotoxic activity.Adefovirdipivoxil can be treated the hepatitis B virus to lamivudine resistance, and can effectively control drug resistance to lamivudine with the lamivudine therapeutic alliance.
Adefovir ester is a kind of multiple crystal formation of having of water and unformed solid matter of being insoluble in, and usually degrades along with time lengthening under field conditions (factors), influences drug quality.
The human bioavailability of adefovir ester only is 40%～60%, and tangible nephrotoxicity is arranged.For the patient who is not suitable for oral administration, most at present adefovirdipivoxil ester formulations that use can't reach effective blood drug level.And just can reach effective blood drug concentration rapidly with the administration of non-intestinal mode, suppress hepatitis virus and duplicate relief of symptoms.
Liposome has the phospholipid bilayer structure, have improve encapsulated stability of drug, to the targeting of local diseased region, reduce characteristics such as poisonous side effect of medicine, it is widely used in field of pharmaceutical preparations.Especially to point out, lipid physical ability selectivity concentrates on mononuclear phagocyte system, major part concentrates on liver, medicine by liposome after, concentration in liver just improves greatly, hepatic disease is played good therapeutical effect, significantly reduce the toxicity of medicine simultaneously other internal organs and normal structure.
Therefore, the injection of preparation adefovir dipivoxil liposome knows that preparation is very important.
Summary of the invention
One of purpose of the present invention is at the adefovir ester instability, and the problem of the low and nephrotoxicity of bioavailability provides a kind of adefovir dipivoxil liposome ejection preparation, comprises adefovir dipivoxil liposome injection and adefovir dipivoxil liposome injectable powder;
Another object of the present invention provides the preparation method of described adefovir dipivoxil liposome ejection preparation.
The invention provides a kind of adefovir dipivoxil liposome preparation, said preparation contains adefovir ester, the lipid of preparation liposome, and/or medicine acceptable carrier.Wherein the lipid of adefovir ester and preparation liposome has following percentage by weight:
Adefovir ester 0.01～1%, the lipid 0.05～15% of preparation liposome.
The lipid of described preparation liposome is selected from one or more in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidyl choline, poloxamer, dimyristoyl phosphatidyl choline, brejs nonionic surfactant, the cholesterol; Described medicine acceptable carrier is to make the required proppant of pharmaceutical preparation, is selected from solvent for injection, mannitol, glucose, sorbitol, sucrose, lactose, trehalose, sodium chloride, polyvinylpyrrolidone, albumin, the dextran one or more.
Liposomal formulation of the present invention is an injection, preferably injection of solution agent or powder needle injection.Described injection is a unit dosage form with every injection, contains adefovir ester 0.2～20mg in every injection.
The present invention also provides the preparation method of Liposomal formulation, it is characterized in that, may further comprise the steps:
A. adefovir ester is made lipid soln with the lipid of preparation liposome;
B. lipid soln is made adefovir dipivoxil liposome, or lipid soln is made the adefovir dipivoxil liposome that contains proppant with the aqueous solution that contains proppant;
C. make preparation.
Wherein:
Heating and melting or solvent method are adopted in the preparation of the lipid soln of adefovir ester described in the step a.;
Film dispersion method or fusion method or injection method or reverse evaporation are adopted in the preparation of adefovir dipivoxil liposome described in the step b.;
The described preparation of making of step c is to add solvent for injection, filters, and makes injection adefovir dipivoxil liposome solution, and the adefovir dipivoxil liposome that maybe will contain proppant gets exsiccant adefovir dipivoxil liposome powder pin through lyophilization or spray drying.
Preferably:
Solvent method is adopted in the preparation of the lipid soln of adefovir ester described in the step a., and the lipid components of described preparation liposome is selected from one or more in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidyl choline, poloxamer, dimyristoyl phosphatidyl choline, brejs nonionic surfactant, the cholesterol.
Film dispersion method is adopted in the preparation of adefovir dipivoxil liposome described in the step b., and described proppant is selected from one or more in mannitol, glucose, sorbitol, sucrose, lactose, trehalose, sodium chloride, polyvinylpyrrolidone, albumin, the dextran.
Preferred:
Solvent method is adopted in the preparation of the lipid soln of adefovir ester described in the step a., and the lipid components of described preparation liposome is selected from one or more in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, poloxamer, the cholesterol;
Film dispersion method is adopted in the preparation of adefovir dipivoxil liposome described in the step b., and described proppant is selected from one or more in glucose, sucrose, lactose, sodium chloride, the dextran;
The adefovir dipivoxil liposome that contains proppant in the step c gets exsiccant adefovir dipivoxil liposome powder pin through spray drying.
Adefovir ester Injectable liposomal of the present invention, the crude drug percentage by weight is in the prescription: adefovir ester 0.01～5%, the lipid 0.01～20% of preparation liposome; Preferred feedstock medicine percentage by weight is: adefovir ester 0.01～1%, the lipid 0.05～15% of preparation liposome.
The lipid of described preparation liposome is selected from but is not limited in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidyl choline, poloxamer, dimyristoyl phosphatidyl choline, brejs nonionic surfactant, the cholesterol one or more; Preferably soya lecithin, Ovum Gallus domesticus Flavus lecithin, poloxamer and cholesterol.
The preparation method of adefovir ester Injectable liposomal of the present invention may further comprise the steps:
A) get adefovir ester and make lipid soln with the lipid of preparation liposome;
B) lipid soln is made adefovir dipivoxil liposome;
C) get adefovir dipivoxil liposome, add water for injection, filter, make the injection adefovir dipivoxil liposome.
Wherein, heating and melting or solvent method are adopted in the preparation of the lipid soln of adefovir ester described in the step a);
Film dispersion method or fusion method or injection method or reverse evaporation are adopted in the preparation of adefovir dipivoxil liposome described in the step b).
Preferred manufacturing procedure may further comprise the steps:
A) adefovir ester is made lipid soln with the lipid of preparation liposome;
B) lipid soln is made adefovir dipivoxil liposome;
C) adefovir dipivoxil liposome adds water for injection, filters, and makes the injection adefovir dipivoxil liposome.
Wherein, solvent method is adopted in the preparation of the lipid soln of adefovir ester described in the step a);
Film dispersion method is adopted in the preparation of adefovir dipivoxil liposome described in the step b).
Adefovir dipivoxil liposome injectable powder of the present invention is made of the lipid and the proppant of adefovir ester, preparation liposome.
The preparation method of described adefovir dipivoxil liposome powder pin is:
A) get adefovir ester and make lipid soln with the lipid of preparation liposome;
B) lipid soln is made the adefovir dipivoxil liposome that contains proppant with the aqueous solution that contains proppant;
C) adefovir dipivoxil liposome that contains proppant gets exsiccant adefovir dipivoxil liposome powder pin through lyophilization or spray drying.
Wherein, the lipid of the preparation liposome described in the step a) is selected from one or more in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidyl choline, poloxamer, dimyristoyl phosphatidyl choline, brejs nonionic surfactant, the cholesterol.
Proppant described in the step b) is selected from one or more in mannitol, glucose, sorbitol, sucrose, lactose, trehalose, sodium chloride, polyvinylpyrrolidone, albumin, the dextran.
Preferably, the preparation method of adefovir dipivoxil liposome powder pin of the present invention is:
A) get adefovir ester and make lipid soln by heating and melting or solvent method with the lipid of preparation liposome;
B) lipid soln is made the adefovir dipivoxil liposome that contains proppant with the aqueous solution that contains proppant by film dispersion method or fusion method or injection method or reverse evaporation;
C) adefovir dipivoxil liposome of proppant gets exsiccant adefovir dipivoxil liposome powder pin through lyophilization or spray drying.
Wherein, the lipid of the preparation liposome described in the step a) is selected from but is not limited in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, poloxamer, dimyristoyl phosphatidyl choline, the cholesterol one or more.
Proppant described in the step b) is selected from one or more in mannitol, glucose, sorbitol, sucrose, lactose, sodium chloride, the dextran.
Best, the preparation method of adefovir dipivoxil liposome powder pin of the present invention is:
A) get adefovir ester and make lipid soln by solvent method with the lipid of preparation liposome;
B) lipid soln is made the adefovir dipivoxil liposome that contains proppant with the aqueous solution that contains proppant by film dispersion method;
C) adefovir dipivoxil liposome of proppant gets exsiccant adefovir dipivoxil liposome powder pin through spray drying.
Wherein, the lipid of the preparation liposome described in the step a) is selected from one or more in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, poloxamer, the cholesterol.
Proppant described in the step b) is selected from one or more in glucose, sucrose, lactose, sodium chloride, the dextran.
The adefovir dipivoxil liposome powder pin that the present invention is made adds a certain amount of water for injection or aqueous solution for injection, after the vibration hydration, promptly gets adefovir ester Injectable liposomal of the present invention.
Adefovir dipivoxil liposome injection provided by the invention and powder pin thereof, its specification are that per unit contains adefovir ester 0.2～20mg.
Adefovir dipivoxil liposome ejection preparation of the present invention has following advantage:
(1) liposome is rolled in pharmaceutical pack in the middle of the lipid bimolecular, can avoid the destruction of unstable factors such as light, oxygen, acid, alkali to medicine, thereby improves stability of drug.In addition, liposome powder pin is a solid preparation, can solve the instability problem of the gathering, sedimentation, fusion, seepage etc. of conventional liposome.
(2) bioavailability of raising adefovir ester.Adefovir ester can overcome the low shortcoming of oral administration bioavailability with the administration of non-intestinal mode; Simultaneously, the patient for unsuitable oral administration with the administration of non-intestinal mode, helps it to reach effective blood drug concentration fast.
(3) improve the curative effect of adefovir ester, the toxic and side effects of reduction adefovir ester.For the adefovir ester that obvious nephrotoxicity is arranged, its lipid physical ability selectivity concentrates on mononuclear phagocyte system, and major part concentrates on the i.e. height targeting liver of liver, thereby is effectively reducing its toxicity to kidney in the treatment hepatic disease.
The specific embodiment
Further specify the present invention below in conjunction with embodiment, but the scope of the inventive method is not limited to following example.
Embodiment 1: the preparation of adefovir dipivoxil liposome injection
Take by weighing adefovir ester 3g, soybean lecithin 20g and cholesterol 7g put in the round-bottomed flask, add an amount of ethanol and make to the above-mentioned mixture and be dissolved into clear and bright solution fully, put water bath with thermostatic control (75 ℃) drying under reduced pressure film forming, add 1000ml water for injection dissolving film, carry out homogenate with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, the reuse filtering with microporous membrane is sub-packed in the ampoule (or cillin bottle), makes every bottle to contain adefovir ester 6mg, sterilization promptly gets the adefovir ester Injectable liposomal.
Embodiment 2: the preparation of adefovir dipivoxil liposome injection
Take by weighing adefovir ester 1g, Ovum Gallus domesticus Flavus lecithin 30g and cholesterol 30g put in the round-bottomed flask, add an amount of chloroform and make to the above-mentioned mixture and be dissolved into clear and bright solution fully, put water bath with thermostatic control (75 ℃) drying under reduced pressure film forming, add 1000ml water for injection dissolving film, carry out homogenate with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, the reuse filtering with microporous membrane is sub-packed in the ampoule (or cillin bottle), makes every bottle to contain adefovir ester 2mg, sterilization promptly gets the adefovir ester Injectable liposomal.
Example 3: the preparation of adefovir dipivoxil liposome injection
Take by weighing adefovir ester 3g, Ovum Gallus domesticus Flavus lecithin 30g, cholesterol 30g and F
6827g puts in the round-bottomed flask, adding an amount of chloroform makes to the above-mentioned mixture and is dissolved into clear and bright solution fully, put water bath with thermostatic control (75 ℃) drying under reduced pressure film forming, add 1000ml water for injection dissolving film, carry out homogenate with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, the reuse filtering with microporous membrane, be sub-packed in the ampoule (or cillin bottle), make every bottle to contain adefovir ester 2mg, sterilization promptly gets the adefovir ester Injectable liposomal.
Example 4: the preparation of adefovir dipivoxil liposome injection
Take by weighing adefovir ester 10g, soybean lecithin 10g puts in the round-bottomed flask, add an amount of chloroform and make to the above-mentioned mixture and be dissolved into clear and bright solution fully, put water bath with thermostatic control (75 ℃) drying under reduced pressure film forming, add 980ml water for injection dissolving film, carry out homogenate with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, the reuse filtering with microporous membrane is sub-packed in the ampoule (or cillin bottle), makes every bottle to contain adefovir ester 6mg, sterilization promptly gets the adefovir ester Injectable liposomal.
Embodiment 5: the preparation of adefovir dipivoxil liposome injection
Take by weighing adefovir ester 0.1g, F
680.1g put in the round-bottomed flask, adding an amount of ethanol makes to the above-mentioned mixture and is dissolved into clear and bright solution fully, put water bath with thermostatic control (75 ℃) drying under reduced pressure film forming, add 1000ml water for injection dissolving film, carry out homogenate with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, the reuse filtering with microporous membrane, be sub-packed in the ampoule (or cillin bottle), make every bottle to contain adefovir ester 2mg, sterilization promptly gets the adefovir ester Injectable liposomal.
Embodiment 6: the preparation of adefovir dipivoxil liposome injection
Take by weighing adefovir ester 50g, dimyristoyl phosphatidyl choline 100g, cholesterol 50g puts in the round-bottomed flask, adds an amount of ethanol and makes to the above-mentioned mixture and be dissolved into clear and bright solution fully, put water bath with thermostatic control (75 ℃) drying under reduced pressure film forming, add 800ml water for injection dissolving film, carry out homogenate with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, the reuse filtering with microporous membrane, be sub-packed in the ampoule (or cillin bottle), make every bottle to contain adefovir ester 6mg, sterilization promptly gets the adefovir ester Injectable liposomal.
Embodiment 7: the preparation of adefovir dipivoxil liposome injection
Take by weighing adefovir ester 5g, Ovum Gallus domesticus Flavus lecithin 5g, F
6810g puts in the round-bottomed flask, adding an amount of chloroform makes to the above-mentioned mixture and is dissolved into clear and bright solution fully, put water bath with thermostatic control (75 ℃) drying under reduced pressure film forming, add 980ml water for injection dissolving film, carry out homogenate with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, the reuse filtering with microporous membrane, be sub-packed in the ampoule (or cillin bottle), make every bottle to contain adefovir ester 4mg, sterilization promptly gets the adefovir ester Injectable liposomal.
Embodiment 8: the preparation of adefovir dipivoxil liposome injection
Take by weighing adefovir ester 5g, soybean lecithin 0.5g puts in the round-bottomed flask, add an amount of chloroform and make to the above-mentioned mixture and be dissolved into clear and bright solution fully, put water bath with thermostatic control (75 ℃) drying under reduced pressure film forming, add 2000ml water for injection dissolving film, carry out homogenate with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, the reuse filtering with microporous membrane is sub-packed in the ampoule (or cillin bottle), makes every bottle to contain adefovir ester 2mg, sterilization promptly gets the adefovir ester Injectable liposomal.
Embodiment 9: the preparation of adefovir dipivoxil liposome injection
Take by weighing adefovir ester 0.2g, distearoyl phosphatidylcholine 0.1g puts in the round-bottomed flask, add an amount of ethanol and make to the above-mentioned mixture and be dissolved into clear and bright solution fully, put water bath with thermostatic control (75 ℃) drying under reduced pressure film forming, add 1000ml water for injection dissolving film, carry out homogenate with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, the reuse filtering with microporous membrane is sub-packed in the ampoule (or cillin bottle), makes every bottle to contain adefovir ester 2mg, sterilization promptly gets the adefovir ester Injectable liposomal.
Embodiment 10: the preparation of adefovir dipivoxil liposome injection
Take by weighing adefovir ester 20g, dipalmitoyl phosphatidyl choline 100g, dimyristoyl phosphatidyl choline 50g and cholesterol 50g put in the round-bottomed flask, adding an amount of ethanol makes to the above-mentioned mixture and is dissolved into clear and bright solution fully, put water bath with thermostatic control (75 ℃) drying under reduced pressure film forming, add 800ml water for injection dissolving film, carry out homogenate with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, the reuse filtering with microporous membrane, be sub-packed in the ampoule (or cillin bottle), make every bottle to contain adefovir ester 6mg, sterilization promptly gets the adefovir ester Injectable liposomal.
Embodiment 11: the preparation of adefovir dipivoxil liposome injectable powder
Take by weighing adefovir ester 5g, soybean lecithin 20g and cholesterol 7g put in the round-bottomed flask, add an amount of ethanol and make to the above-mentioned mixture and be dissolved into clear and bright solution fully, and it is standby to put water bath with thermostatic control (75 ℃) drying under reduced pressure film forming.With 1000ml water for injection dissolving 180g trehalose, filter, with dissolving film in the filtrate impouring round-bottomed flask, carry out homogenate with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, reuse filtering with microporous membrane, degerming, be sub-packed in the ampoule (or cillin bottle), make every bottle to contain adefovir ester 6mg, carry out lyophilization, logical noble gas seals and promptly gets adefovir ester Injectable liposomal powder pin.
Example 12: the preparation of adefovir dipivoxil liposome injectable powder
Take by weighing adefovir ester 1g, Ovum Gallus domesticus Flavus lecithin 30g and cholesterol 30g put in the round-bottomed flask, add an amount of chloroform and make to the above-mentioned mixture and be dissolved into clear and bright solution fully, and it is standby to put water bath with thermostatic control (75 ℃) drying under reduced pressure film forming.With 1000ml water for injection dissolving 200g glucose, filter, with dissolving film in the filtrate impouring round-bottomed flask, carry out homogenate with ultrasonoscope Ultrasonic Pulverization or high-pressure homogenization pump, reuse filtering with microporous membrane, degerming, carry out spray drying, aseptic subpackaged in ampoule (or cillin bottle), make every bottle to contain adefovir ester 2mg, logical noble gas seals and promptly gets adefovir ester Injectable liposomal powder pin.
Claims (10)
1, a kind of adefovir dipivoxil liposome preparation is characterized in that, described Liposomal formulation contains adefovir ester, the lipid of preparation liposome, and/or medicine acceptable carrier.
2, the described Liposomal formulation of claim 1 is characterized in that, wherein the lipid of adefovir ester and preparation liposome has following percentage by weight:
Adefovir ester 0.01～1%, the lipid 0.05～15% of preparation liposome.
3, the described Liposomal formulation of claim 2, it is characterized in that the lipid of described preparation liposome is selected from one or more in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidyl choline, poloxamer, dimyristoyl phosphatidyl choline, brejs nonionic surfactant, the cholesterol; Described medicine acceptable carrier is to make the required proppant of pharmaceutical preparation, is selected from solvent for injection, mannitol, glucose, sorbitol, sucrose, lactose, trehalose, sodium chloride, polyvinylpyrrolidone, albumin, the dextran one or more.
4, any one Liposomal formulation of claim 1-3 is characterized in that, is injection.
5, the described Liposomal formulation of claim 4 is characterized in that, is injection of solution agent or powder needle injection.
6, the described Liposomal formulation of claim 4 is characterized in that, described injection is a unit dosage form with every injection, contains adefovir ester 0.2～20mg in every injection.
7, the preparation method of the Liposomal formulation of claim 1 is characterized in that, may further comprise the steps:
A. adefovir ester is made lipid soln with the lipid of preparation liposome;
B. lipid soln is made adefovir dipivoxil liposome, or lipid soln is made the adefovir dipivoxil liposome that contains proppant with the aqueous solution that contains proppant;
C. make preparation.
8, the preparation method of claim 7 is characterized in that,
Heating and melting or solvent method are adopted in the preparation of the lipid soln of adefovir ester described in the step a.;
Film dispersion method or fusion method or injection method or reverse evaporation are adopted in the preparation of adefovir dipivoxil liposome described in the step b.;
The described preparation of making of step c is to add solvent for injection, filters, and makes injection adefovir dipivoxil liposome solution, and the adefovir dipivoxil liposome that maybe will contain proppant gets exsiccant adefovir dipivoxil liposome powder pin through lyophilization or spray drying.
9, the preparation method of claim 7 is characterized in that,
Solvent method is adopted in the preparation of the lipid soln of adefovir ester described in the step a., and the lipid components of described preparation liposome is selected from one or more in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, distearoyl phosphatidylcholine, dipalmitoyl phosphatidyl choline, poloxamer, dimyristoyl phosphatidyl choline, brejs nonionic surfactant, the cholesterol;
Film dispersion method is adopted in the preparation of adefovir dipivoxil liposome described in the step b., and described proppant is selected from one or more in mannitol, glucose, sorbitol, sucrose, lactose, trehalose, sodium chloride, polyvinylpyrrolidone, albumin, the dextran.
10, the preparation method of claim 7 is characterized in that,
Solvent method is adopted in the preparation of the lipid soln of adefovir ester described in the step a., and the lipid components of described preparation liposome is selected from one or more in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, poloxamer, the cholesterol;
Film dispersion method is adopted in the preparation of adefovir dipivoxil liposome described in the step b., and described proppant is selected from one or more in glucose, sucrose, lactose, sodium chloride, the dextran;
The adefovir dipivoxil liposome that contains proppant in the step c gets exsiccant adefovir dipivoxil liposome powder pin through spray drying.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101632639B (en) * | 2009-06-03 | 2011-01-19 | 邓菊娟 | Tinidazole liposome injection and preparation method thereof |
| CN102068410A (en) * | 2011-01-04 | 2011-05-25 | 海南美大制药有限公司 | Solid preparation of ade fovird ip iv oxil liposome |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1830448B (en) * | 2004-12-16 | 2011-08-31 | 沈阳药科大学 | Aldfuwei ester injection having liver target and its preparation method |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101632639B (en) * | 2009-06-03 | 2011-01-19 | 邓菊娟 | Tinidazole liposome injection and preparation method thereof |
| CN102068410A (en) * | 2011-01-04 | 2011-05-25 | 海南美大制药有限公司 | Solid preparation of ade fovird ip iv oxil liposome |
| CN102068410B (en) * | 2011-01-04 | 2012-05-09 | 海南美大制药有限公司 | Solid preparation of ade fovird ip iv oxil liposome |
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