CN115475142A - Oral methotrexate liposome and preparation method thereof - Google Patents
Oral methotrexate liposome and preparation method thereof Download PDFInfo
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- CN115475142A CN115475142A CN202211210046.7A CN202211210046A CN115475142A CN 115475142 A CN115475142 A CN 115475142A CN 202211210046 A CN202211210046 A CN 202211210046A CN 115475142 A CN115475142 A CN 115475142A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses an oral methotrexate liposome and a preparation method thereof, wherein the oral methotrexate liposome is prepared from the following raw materials in parts by weight: 15 to 25 portions of methotrexate, 110 to 130 portions of soybean lecithin, 25 to 35 portions of phosphatidylserine with the purity of more than 89 percent, 15 to 25 portions of sodium deoxycholate solution with the pH value of 7.4 and the concentration of 20mmoL/L, 70 to 80 portions of cholesterol and 2000 to 2200 portions of anhydrous ether. The invention adopts a reverse evaporation method to prepare the oral methotrexate liposome, can reduce renal excretion and metabolism, prolong the detention time of the medicine in blood, and slowly release the methotrexate in vivo, thereby prolonging the action time of the medicine, properly reducing the administration times, reducing the side effect, improving the safety and effectiveness of the medicine, relieving the pain of patients and improving the compliance of the patients.
Description
The application is a divisional application with application date of 20/11/2017, application number of 201711235090.2 and invention name of 'an oral methotrexate liposome and a preparation method thereof'.
Technical Field
The invention belongs to the field of medicines, and particularly relates to an oral methotrexate liposome and a preparation method thereof.
Background
Methotrexate (MTX) is an antitumor drug with folate reductase inhibitory activity, widely used for the treatment of lymphomas and leukemias, and for the treatment of cervical, breast, lung, head and neck and ovarian tumors, but with low safety, and has serious adverse reactions, mainly: 1. gastrointestinal tract reaction: stomatitis, aphthous ulcer, pharyngolaryngitis, nausea, vomiting, abdominal pain, diarrhea, gastrointestinal hemorrhage, occasional pseudomembranous or hemorrhagic enteritis, etc.; 2. impaired liver function: increased jaundice, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, etc.; 3. when applied in large dose, the product and metabolite are deposited in renal tubule to cause hyperuricemia nephropathy, which may appear as hematuria, proteinuria, oliguria, azotemia or even uremia. The dosage is the key reason of death, because the dosage difference is larger when MTX is used for treating different diseases, the dosage for treating malignant tumor is 15 or 30mg/m 2 The preparation is administered orally or by injection, and the maximum dose can be 500mg/m by intravenous injection 2 (ii) a The dosage of the medicine for treating acute lymphatic leukemia of children can be increased to 5000mg/m 2 (ii) a The individual difference is large, and the blood concentration is unstable; a large number of literature reports: the toxic reaction can be minimized by using MTX 72h blood concentration lower than 0.1 mu mol/L.
MTX efficacy and toxicity are therefore dependent on Cmax and Tmax; the common dosage form and the administration route cause the lack of slow release, the blood concentration is either lower than Cmin or higher than Cmax, and the targeting property is lacked. Both of them lead to increased toxicity and decreased efficacy.
The liposome as an advanced drug carrier has main clinical advantages that: enhancing the solubility of the drug; the toxicity of the medicine is reduced; endowing the medicine with targeting property; the slow release function of the medicine; improving the protection effect on the medicine; the drug is delivered into the cytoplasm or nucleus by fusion.
There are also some disadvantages to ordinary liposomes: (1) having dose-dependent pharmacokinetic characteristics; (2) Physical stability in vitro and chemical stability in vivo (oral administration is easy to be damaged by digestive juice in gastrointestinal tract) are poor; (3) After intravenous administration, the medicine is easily phagocytized by macrophages in MPS, and has very short half-life in systemic circulation, thus having poor targeted therapeutic effect on target organs such as tumor and the like. These disadvantages limit the application of the common liposome as the carrier of anticancer drugs in tumor chemotherapy to a certain extent. How to reduce or avoid the interaction between the common liposome and various components in the surrounding medium, reduce the phagocytosis by MPS in vivo, improve the stability in vitro and in vivo, prolong the circulation time in vivo, and ensure that the concentration of the drug in the target organ is high and the concentration of the drug in the non-target tissue is low is the key and difficult point of the current liposome research.
Disclosure of Invention
The invention aims to provide an oral methotrexate liposome and a preparation method thereof aiming at the defects of the prior art.
The technical scheme adopted by the invention for realizing the aim is as follows: an oral methotrexate cholate liposome is prepared from the following raw materials in parts by weight: 15-25 parts of methotrexate, 110-130 parts of soybean lecithin, 25-35 parts of phosphatidylserine with the purity of more than 89%, 15-25 parts of sodium deoxycholate solution with the pH value of 7.4 and the concentration of 20mmoL/L, 70-80 parts of cholesterol and 2000-2200 parts of anhydrous ether.
A method for preparing the oral methotrexate cholate liposome adopts a reverse evaporation method, and comprises the following steps:
(1) Preparing a phosphate buffer solution with the pH value of 7.4; adding 11.876g/L disodium hydrogen phosphate into 9.078g/L sodium dihydrogen phosphate, wherein the volume ratio of the disodium hydrogen phosphate to the sodium dihydrogen phosphate is 8:2, obtaining phosphate buffer solution with pH =7.4 for later use;
(2) Preparing a phosphate buffer solution of sodium deoxycholate with the pH value of 7.4 for later use; adding 20mmoL/L sodium deoxycholate solution into phosphate buffer solution with pH =7.4 to obtain 20mmoL/L sodium deoxycholate solution -1 Phosphate buffer solution with pH value of 7.4 of sodium deoxycholate for standby;
(3) Preparing an organic phase: dissolving soybean lecithin, phosphatidylserine, cholesterol and methotrexate in anhydrous ether to form an organic phase; injecting phosphate buffer solution into the organic phase, performing water bath ultrasound for 5min to form stable W/O-shaped emulsion; and (3) placing the emulsion on a rotary evaporator, removing ether under reduced pressure to obtain a viscous colloidal solution, adding a phosphate buffer solution of sodium deoxycholate with the pH value of 7.4, and continuing to evaporate under reduced pressure to obtain the methotrexate cholate liposome.
The principle of the invention is as follows: the greatest difficulty encountered with liposomes when administered orally is the digestive action of the gastrointestinal tract. Before the liposome does not enter the systemic circulation, the liposome needs to be damaged by gastric acid and bile salts in the gastrointestinal tract, bile secreted by the liver has the strongest digestion effect on the liposome, digestive enzymes do not exist in the bile, and sodium salt or potassium salt (bile salt) formed by combining bile acid with glycine or taurine is a main component of the bile participating in digestion and absorption of fatty substances. Thus, the preparation of bile salt liposomes can provide another requirement for the oral administration of liposomes. Proper bile salt is added in the process of preparing the liposome, and becomes a part of a bilayer membrane, so that the bile salt can exchange with endogenous bile salt in the gastrointestinal tract to be finally balanced, and the liposome is prevented from being digested by the bile salt.
The MTX liposome preparation is prepared by encapsulating MTX molecules into liposome, thereby improving the stability of the drug and playing the roles of slow release and passive targeting. Because MTX is a fat-soluble drug and can be inserted between lipid bilayer membranes to solubilize the MTX in water, the liposome-encapsulated drug can reduce the toxic and side effects of the drug, increase the distribution of drug molecules at tumor sites and reduce the toxicity of the drug molecules to other normal tissues. The medicine is encapsulated into liposome, so that renal excretion and metabolism can be reduced, the residence time of the medicine in blood can be prolonged, and the medicine can be slowly released in vivo, so that the action time of the medicine can be prolonged, the administration times can be properly reduced, the side effect can be reduced, the safety and the effectiveness of the medicine can be improved, the pain of a patient can be relieved, and the compliance of the patient can be improved.
Drawings
FIG. 1 is a graph of the dosing time for four MTX formulations of the present invention.
FIG. 2 shows four major pharmacokinetic parameters of MTX according to the invention.
FIG. 3 is a chart showing the concentration of MTX common liposome and bile salt liposome drug in the present invention.
Detailed Description
The present invention will be further described with reference to examples.
Example 1
The oral methotrexate cholate liposome is prepared from the following raw materials in parts by weight: 16 parts of methotrexate, 112 parts of soybean lecithin, 27 parts of phosphatidylserine with the purity of more than 89%, 16 parts of sodium deoxycholate solution with the pH value of 7.4 and the concentration of 20mmoL/L, 72 parts of cholesterol and 2050 parts of anhydrous ethyl ether.
The preparation method of the oral methotrexate cholate liposome adopts a reverse evaporation method, and comprises the following steps:
(1) Preparing a phosphate buffer solution with the pH value of 7.4; adding 11.876g/L disodium hydrogen phosphate into 9.078g/L sodium dihydrogen phosphate, wherein the volume ratio of the disodium hydrogen phosphate to the sodium dihydrogen phosphate is 8:2, obtaining a phosphate buffer solution with the pH =7.4 for later use;
(2) Preparing a phosphate buffer solution of sodium deoxycholate with the pH value of 7.4 for later use; adding 20mmoL/L sodium deoxycholate solution into phosphate buffer solution with pH =7.4 to obtain 20mmoL/L sodium deoxycholate solution -1 Phosphate buffer solution with pH value of 7.4 of sodium deoxycholate for standby;
(3) Preparing an organic phase: dissolving soybean lecithin, phosphatidylserine, cholesterol and methotrexate in anhydrous ether to form an organic phase; injecting phosphate buffer solution into the organic phase, performing water bath ultrasound for 5min to form stable W/O-shaped emulsion; and (3) placing the emulsion on a rotary evaporator, removing ether under reduced pressure to obtain a viscous colloidal solution, adding a phosphate buffer solution of sodium deoxycholate with the pH value of 7.4, and continuously evaporating under reduced pressure to obtain the methotrexate cholate liposome.
Example 2
The oral methotrexate cholate liposome is prepared from the following raw materials in parts by weight: 19 parts of methotrexate, 120 parts of soybean lecithin, 29 parts of phosphatidylserine with the purity of more than 89%, 20 parts of sodium deoxycholate solution with the pH value of 7.4 and the concentration of 20mmoL/L, 75 parts of cholesterol and 2100 parts of anhydrous ethyl ether; the preparation method is the same as that of example 1.
Example 3
The pterin bile salt liposome is prepared from the following raw materials in parts by weight: methotrexate 22 parts, soybean lecithin 125 parts, phosphatidylserine 32 parts with the purity of more than 89%, sodium deoxycholate solution with the pH value of 7.4 and the concentration of 20 mmoL/L22 parts, cholesterol 77 parts and anhydrous ether 2150 parts, and the preparation method is the same as that of example 1.
Example 4
The oral methotrexate cholate liposome is prepared from the following raw materials in parts by weight: 24 parts of methotrexate, 129 parts of soybean lecithin, 34 parts of phosphatidylserine with the purity of more than 89%, 24 parts of sodium deoxycholate solution with the pH value of 7.4 and the concentration of 20mmoL/L, 79 parts of cholesterol and 2200 parts of anhydrous ethyl ether; the preparation method is the same as that of example 1.
The experimental results of the rats orally administered methotrexate cholate liposome prepared above are as follows:
the MTX solution, MTX ordinary liposome, MTX chitosan coated liposome and MTX bile salt liposome are respectively administered by intragastric perfusion, blood samples are taken and processed by HPLC and corresponding software, and the results are shown in figure 1 and figure 2:
pharmacokinetic results show that: the peak concentration of the chitosan coated liposome is maximum, the t1/2 of the cholate liposome and the chitosan liposome are respectively 1.56 and 1.93 times of that of the common liposome group, and the AUC is obviously prolonged 0-∞ (ii) a The two are respectively 1.94 and 3.3 times of the common liposome, and the statistical analysis shows that the two have significant difference (P is less than 0.00I); cmax/AUC 0-∞ Generally representing the absorption rate, the data is known as: MTX Normal liposome group absorption RateThe bile salt liposome has the functions of delaying medicine release and improving bioavailability compared with common liposome.
In vitro release
Placing 1mL of MTX common liposome and bile salt liposome in dialysis bag, and placing the dialysis bag in 0.1 mol.L -1 The release test was performed in hydrochloric acid, and the drug concentration was measured by HPLC. The results of the experiment are shown in FIG. 3.
As can be seen from fig. 3, in the hydrochloric acid solution, the release rate of the bile salt liposome is slower than that of the general liposome.
Although the present invention has been described in detail with reference to the above embodiments, it is only a part of the embodiments of the present invention, not all of the embodiments, and other embodiments can be obtained without inventive step according to the embodiments, and the embodiments are within the scope of the present invention.
Claims (6)
1. A preparation method of the oral methotrexate cholate liposome is characterized in that: the preparation method adopts a reverse evaporation method, and comprises the following steps:
(1) Preparation of phosphate buffer at pH 7.4: adding 11.876g/L disodium hydrogen phosphate into 9.078g/L sodium dihydrogen phosphate, wherein the volume ratio of the disodium hydrogen phosphate to the sodium dihydrogen phosphate is 8:2, obtaining phosphate buffer solution with the pH =7.4 for later use;
(2) Preparing a phosphate buffer solution of sodium deoxycholate with the pH value of 7.4 for later use; adding 20mmoL/L sodium deoxycholate solution into phosphate buffer solution with pH =7.4 to obtain 20mmoL/L sodium deoxycholate solution -1 Phosphate buffer solution with pH value of 7.4 of sodium deoxycholate for standby;
(3) Preparing an organic phase: dissolving soybean lecithin, phosphatidylserine, cholesterol and methotrexate in anhydrous ether to form an organic phase; injecting phosphate buffer solution into the organic phase, and performing water bath ultrasound for 5min to form stable W/O-shaped emulsion; placing the emulsion on a rotary evaporator, removing ether under reduced pressure to obtain viscous colloidal solution, adding sodium deoxycholate phosphate buffer solution with pH of 7.4, and continuing to evaporate under reduced pressure to obtain methotrexate cholate liposome;
the oral methotrexate cholate liposome is prepared from the following raw materials in parts by weight: 15-25 parts of methotrexate; 110-130 parts of soybean lecithin; 25-35 parts of phosphatidylserine with the purity of more than 89%; 15-25 parts of sodium deoxycholate solution with the pH value of 7.4 and the concentration of 20 mmoL/L; 70-80 parts of cholesterol; 2000-2200 parts of anhydrous ether.
2. The production method according to claim 1, characterized in that: the oral methotrexate cholate liposome is prepared from the following raw materials in parts by weight: 16 parts of methotrexate, 112 parts of soybean lecithin, 27 parts of phosphatidylserine with the purity of more than 89%, 16 parts of sodium deoxycholate solution with the pH value of 7.4 and the concentration of 20mmoL/L, 72 parts of cholesterol and 2050 parts of anhydrous ether.
3. The method of claim 1, wherein: the oral methotrexate cholate liposome is prepared from the following raw materials in parts by weight: 19 parts of methotrexate, 120 parts of soybean lecithin, 29 parts of phosphatidylserine with the purity of more than 89%, 20 parts of sodium deoxycholate solution with the pH value of 7.4 and the concentration of 20mmoL/L, 75 parts of cholesterol and 2100 parts of anhydrous ether.
4. The method of claim 1, wherein: the oral methotrexate cholate liposome is prepared from the following raw materials in parts by weight: 22 parts of methotrexate, 125 parts of soybean lecithin, 32 parts of phosphatidylserine with the purity of more than 89%, 22 parts of sodium deoxycholate solution with the pH value of 7.4 and the concentration of 20mmoL/L, 77 parts of cholesterol and 2150 parts of anhydrous ether.
5. The production method according to claim 1, characterized in that: the oral methotrexate cholate liposome is prepared from the following raw materials in parts by weight: 24 parts of methotrexate, 129 parts of soybean lecithin, 34 parts of phosphatidylserine with the purity of more than 89%, 24 parts of sodium deoxycholate solution with the pH value of 7.4 and the concentration of 20mmoL/L, 79 parts of cholesterol and 2200 parts of anhydrous ether.
6. Oral methotrexate cholate liposomes obtained by the production method according to any one of claims 1 to 5.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008030818A2 (en) * | 2006-09-05 | 2008-03-13 | Mebiopharm Co., Ltd. | Novel liposome compositions |
| CN102924456A (en) * | 2007-01-18 | 2013-02-13 | 萨维法姆公司 | Compositions and methods of reducing side effects and toxicity of methotrexate when given as orotate derivatives |
| CN107007553A (en) * | 2017-05-19 | 2017-08-04 | 泰山医学院 | A kind of polysaccharide cholate liposome for being used to be administered orally and preparation method thereof |
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| US9770414B2 (en) * | 2010-05-13 | 2017-09-26 | Pacira Pharmaceuticals, Inc. | Sustained release formulation of methotrexate as a disease-modifying antirheumatic drug (DMARD) and an anti-cancer agent |
| CN102631319B (en) * | 2012-04-24 | 2013-09-18 | 吉林大学珠海学院 | Phellinus linteus polysaccharide oral liposome medicine and preparation technology thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008030818A2 (en) * | 2006-09-05 | 2008-03-13 | Mebiopharm Co., Ltd. | Novel liposome compositions |
| CN102924456A (en) * | 2007-01-18 | 2013-02-13 | 萨维法姆公司 | Compositions and methods of reducing side effects and toxicity of methotrexate when given as orotate derivatives |
| CN107007553A (en) * | 2017-05-19 | 2017-08-04 | 泰山医学院 | A kind of polysaccharide cholate liposome for being used to be administered orally and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| 朱林等: "甲氨蝶呤磁靶向脂质体的制备及初步评价", 中国药学杂志, vol. 41, no. 17, pages 1324 - 1327 * |
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