CN114246840A - Oral paclitaxel capsule - Google Patents

Oral paclitaxel capsule Download PDF

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Publication number
CN114246840A
CN114246840A CN202010999346.2A CN202010999346A CN114246840A CN 114246840 A CN114246840 A CN 114246840A CN 202010999346 A CN202010999346 A CN 202010999346A CN 114246840 A CN114246840 A CN 114246840A
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Prior art keywords
paclitaxel
capsule
oral
organic solvent
amphiphilic polymer
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郝贵周
李学鹏
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Lunan Pharmaceutical Group Corp
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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an oral paclitaxel capsule and a preparation method thereof. Dissolving paclitaxel, amphiphilic polymer carrier and oil phase in organic solvent at selected ratio to obtain homogeneous solution, removing organic solvent by rotary evaporation, encapsulating in soft capsule, and coating enteric coating. After the paclitaxel enteric-coated capsule enters the intestinal tract, the drug-containing compound spontaneously forms nanoemulsion in intestinal juice, so that the fat solubility is increased, transmembrane transport is easy, and lymphatic transport is increased. The paclitaxel capsule for oral administration prepared by the invention can obviously improve the bioavailability of paclitaxel; the surfactant which is easy to cause anaphylactic reaction of human bodies is not contained, so that the medication safety is improved; simple preparation process, convenient administration and good stability.

Description

Oral paclitaxel capsule
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an oral paclitaxel capsule and a preparation method thereof.
Background
Paclitaxel is a diterpene isolated from the Pacific yew tree (Taxus brevifolia). Because paclitaxel binds to tubulin, paclitaxel has the ability to inhibit cell division. Thus, paclitaxel has been approved for the treatment of ovarian, breast, lung, head and neck, and pancreatic cancers. However, the solubility of paclitaxel in water is very low, which makes it difficult to formulate a safe and effective therapeutic approach.
Paclitaxel cannot be taken orally and has low bioavailability due to its very low solubility (< 1 μ g/mL) and poor gastrointestinal barrier permeability. The paclitaxel preparation used in clinic at present is intravenous injection. For example, the commercially available preparation Taxol (Taxol) is a colorless viscous solution prepared from polyoxyethylated castor oil/absolute ethanol (50/50). However, the polyoxyethylated castor oil in the formulation causes serious side effects such as allergic reactions, neurotoxicity and nephrotoxicity in patients. In order to reduce the toxicity of paclitaxel preparations and improve the curative effect thereof, new formulations of paclitaxel have been developed in recent years. The castor oil injection paclitaxel albumin nanometer suspension without polyoxyethylene is sold in the market at home and abroad, and has the characteristics of no need of antiallergic pretreatment, better curative effect, lower toxicity and the like; paclitaxel liposome developed in China is also on the market; the Korean marketed paclitaxel polymer micelle dosage form Genex-PM also shows good prospects.
Compared with the administration mode by injection, the oral administration mode is more easily accepted by people due to the characteristics of no pain, self administration and the like with good compliance. In addition, oral absorption is a normal physiological absorption mode of the gastrointestinal tract, and the oral absorption enters blood through the intestinal liver, so that the defects of disease transmission, high blood concentration and the like possibly caused by an injection administration mode are avoided. Therefore, researchers have adopted many strategies to improve the oral bioavailability of paclitaxel. Chinese patent CN108697683A discloses a method for preparing oral taxane composition, but the preparation process uses a large amount of surfactant such as polysorbate 80, polyoxyethylene castor oil, etc. which are liable to cause allergic reaction in human body, and the bioavailability is low. Chinese patent CN100544714C discloses a composition for solubilizing paclitaxel and its preparation method, which also uses emulsifier, surfactant, etc. with certain toxicity; the prepared composition is a coarse dispersion with large particles, and the composition exists as a liquid at the temperature of more than 40 ℃, so that the composition is inconvenient to use clinically. Chinese patent 201911318944.2 discloses a method for preparing oral paclitaxel composite micelle, but p-glycoprotein inhibitors such as cyclosporin and tacrolimus are used in the preparation process, and the stability of the micelle solution is poor, and the bioavailability of paclitaxel is still low.
Overall, there is currently no ideal oral dosage form of paclitaxel.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a capsule capable of improving the oral bioavailability of paclitaxel and a preparation method thereof. Dissolving paclitaxel, amphiphilic polymer carrier and oil phase in organic solvent at selected ratio to obtain homogeneous solution, removing organic solvent by rotary evaporation, encapsulating in soft capsule, and coating enteric coating. After entering the intestinal tract, the drug-containing compound spontaneously forms nanoemulsion in intestinal juice, so that the fat solubility is increased, transmembrane transport is easy, and lymphatic transport is increased. The paclitaxel capsule for oral administration prepared by the invention has simple preparation process, convenient administration and good stability, and can obviously improve the oral bioavailability of paclitaxel.
Specifically, the invention is realized by the following technologies:
an oral paclitaxel capsule is prepared by dispersing amphiphilic polymer as carrier in oil phase, filling into soft capsule, and coating with enteric coating.
The hydrophilic end of the amphiphilic polymer is methoxy polyethylene glycol (mPEG), and the hydrophobic end of the amphiphilic polymer is Polylactide (PLA).
The total weight of the methoxy polyethylene glycol accounts for 20-70 percent of the amphiphilic polymer, and is preferably 50 percent.
The molecular weight of the amphiphilic polymer is 5,000-12,000 daltons, and preferably 8000 daltons.
The oil phase is one or more of medium chain triglyceride, polyethylene glycol oleate, glycerol monolinoleate and glycerol monooleate, and preferably medium chain triglyceride or polyethylene glycol oleate.
The weight ratio of the paclitaxel to the amphiphilic polymer is 1: 5-7, preferably 1: 6.
the weight ratio of the paclitaxel to the oil phase is 1: 30-70, preferably 1: 40 to 50.
In the invention, the oral paclitaxel capsule is prepared by the following specific steps:
a) weighing paclitaxel, amphiphilic polymer and oil phase in the formula amount in an organic solvent, and fully mixing by vortex to obtain a homogeneous solution;
b) the mixture is subjected to rotary evaporation to remove the organic solvent;
c) loading the prepared composite system into soft capsules;
d) the soft capsule is coated with enteric coating.
The organic solvent is one of ethanol, methanol, acetone, chloroform and ethyl acetate, and preferably acetone or ethyl acetate; the temperature of the rotary evaporation is 30-45 ℃.
Compared with the prior art, the invention has the following technical effects:
(1) the prepared oral paclitaxel capsule preparation obviously improves the bioavailability of paclitaxel;
(2) the prepared oral paclitaxel capsule preparation does not contain surfactant and the like which are easy to cause anaphylactic reaction of human bodies, has good biocompatibility, and improves the medication safety;
(3) the preparation process is simple and does not need complex production equipment.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are given solely for the purpose of illustration and not as limitations of the present invention, and therefore, simple modifications of the present invention in the context of the methods of the present invention are intended to fall within the scope of the claims.
Example 1
1) Prescription:
paclitaxel 1g
Medium chain Triglycerides 48g
mPEG4000-PLA4000 6g
2) The preparation method comprises the following steps:
weighing paclitaxel, amphiphilic polymer and medium chain triglyceride according to the prescription amount, adding 30mL acetone, and fully mixing by vortex to obtain homogeneous solution; rotary evaporating at 35 deg.C until the organic solvent is evaporated to dryness; loading the prepared composite system into soft capsules; the soft capsule is coated with enteric coating.
Example 2
1) Prescription:
paclitaxel 1g
Oleic acid polyethylene glycol glyceride 40g
mPEG4000-PLA4000 5g
2) The preparation method comprises the following steps:
weighing paclitaxel, amphiphilic polymer and polyethylene glycol oleate according to the prescription amount, adding 30mL ethyl acetate, and fully mixing by vortex to obtain a homogeneous solution; rotary evaporating at 45 deg.C until the organic solvent is evaporated to dryness; loading the prepared composite system into soft capsules; the soft capsule is coated with enteric coating.
Example 3
1) Prescription:
paclitaxel 1g
Oleic acid polyethylene glycol glyceride 50g
mPEG4000-PLA4000 6g
2) The preparation method comprises the following steps:
weighing paclitaxel, amphiphilic polymer and polyethylene glycol oleate according to the prescription amount, adding 30mL ethyl acetate, and fully mixing by vortex to obtain a homogeneous solution; rotary evaporating at 40 deg.C until the organic solvent is evaporated to dryness; loading the prepared composite system into soft capsules; the soft capsule is coated with enteric coating.
Example 4
1) Prescription:
paclitaxel 1g
Monolinoleate glyceride 30g
mPEG1000-PLA4000 5g
2) The preparation method comprises the following steps:
weighing paclitaxel, amphiphilic polymer and monoglyceride according to the prescription amount, adding 30mL of trichloromethane, and fully mixing by vortex to obtain a homogeneous solution; rotary evaporating at 30 deg.C until the organic solvent is evaporated to dryness; loading the prepared composite system into soft capsules; the soft capsule is coated with enteric coating.
Example 5
1) Prescription:
paclitaxel 1g
Medium chain Triglycerides 70g
mPEG8000-PLA4000 7g
2) The preparation method comprises the following steps:
weighing paclitaxel, amphiphilic polymer and medium chain triglyceride according to the prescription amount, adding 30mL acetonitrile, and fully mixing by vortex to obtain homogeneous solution; rotary evaporating at 45 deg.C until the organic solvent is evaporated to dryness; loading the prepared composite system into soft capsules; the soft capsule is coated with enteric coating.
Example 6
1) Prescription:
Figure BDA0002693722230000041
2) the preparation method comprises the following steps:
weighing paclitaxel, amphiphilic polymer, glycerol monooleate and glycerol monolinoleate according to the prescription amount, adding 30mL of methanol, and fully mixing by vortex to obtain a homogeneous solution; rotary evaporating at 40 deg.C until the organic solvent is evaporated to dryness; loading the prepared composite system into soft capsules; the soft capsule is coated with enteric coating.
Example 7
1) Prescription:
paclitaxel 1g
Medium chain Triglycerides 25g
mPEG2000-PLA2000 4g
2) The preparation method comprises the following steps:
weighing paclitaxel, amphiphilic polymer and medium chain triglyceride according to the prescription amount, adding 30mL ethyl acetate, and fully mixing by vortex to obtain homogeneous solution; rotary evaporating at 45 deg.C until the organic solvent is evaporated to dryness; loading the prepared composite system into soft capsules; the soft capsule is coated with enteric coating.
Example 8
1) Prescription:
paclitaxel 1g
Oleic acid polyethylene glycol glyceride 80g
mPEG3000-PLA3000 8g
2) The preparation method comprises the following steps:
weighing paclitaxel, amphiphilic polymer and polyethylene glycol oleate according to the prescription amount, adding 30mL ethyl acetate, and fully mixing by vortex to obtain a homogeneous solution; rotary evaporating at 45 deg.C until the organic solvent is evaporated to dryness; loading the prepared composite system into soft capsules; the soft capsule is coated with enteric coating.
Example 9
1) Prescription:
paclitaxel 1g
Triolein 30g
mPEG3000-PLGA3000 5g
2) The preparation method comprises the following steps:
weighing paclitaxel, amphiphilic polymer and triolein according to the prescription amount, adding 30mL ethyl acetate, and fully mixing by vortex to obtain a homogeneous solution; rotary evaporating at 45 deg.C until the organic solvent is evaporated to dryness; loading the prepared composite system into soft capsules; the soft capsule is coated with enteric coating.
Comparative example 1
1) Prescription:
paclitaxel 1g
Medium chain Triglycerides 48g
mPEG4000-PLA4000 6g
2) The preparation method comprises the following steps:
weighing paclitaxel, medium-chain triglyceride and amphiphilic polymer according to the prescription amount, adding 30mL ethyl acetate, and fully mixing by vortex to obtain a homogeneous solution; rotary evaporating at 45 deg.C until the organic solvent is evaporated to dryness; and filling the prepared composite system into soft capsules.
Comparative example 2
1) Prescription:
Figure BDA0002693722230000061
2) the preparation method comprises the following steps:
weighing a mixed oil phase of paclitaxel, amphiphilic polymer, glycerol monooleate and tricaprylin according to a prescription amount, adding ethyl acetate according to the prescription amount, and fully mixing in a vortex manner to obtain a homogeneous solution; rotary evaporating at 45 deg.C until the organic solvent is evaporated to dryness; loading the prepared composite system into soft capsules; the soft capsule is coated with enteric coating.
Comparative example 3
1) Prescription:
paclitaxel 1g
mPEG4000-PLA4000 5g
2) The preparation method comprises the following steps:
weighing prescription amount of paclitaxel and mPEG4000-PLA4000Adding 30mL of ethyl acetate, and fully mixing by vortex to obtain a homogeneous solution; the mixture was rotary evaporated to remove ethyl acetate; and (3) filling the prepared composite system into enteric capsules.
Comparative example 4
1) Prescription:
paclitaxel 1g
Medium chain Triglycerides 48g
2) The preparation method comprises the following steps:
weighing paclitaxel and medium chain triglyceride according to the prescription amount, stirring to dissolve into uniform clear solution, and filling the solution into enteric soft capsules; the soft capsule is coated with enteric coating.
Verification examples
1. In vivo bioavailability assay:
comparing the oral paclitaxel capsules and intravenous paclitaxel injection in beagle dogs, the absolute bioavailability of the oral paclitaxel capsules was studied. The beagle dogs are fasted for 12 hours before administration, and when the beagle dogs are injected intravenously, the beagle dogs are injected slowly through forelimb veins at the injection speed of 1 mL/min; collecting blood 0.6mL in forelimb or hindlimb vein after 5min, 10min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 12h, 24h and 48h after administration, performing anticoagulant centrifugation with heparin sodium to collect blood plasma, and storing at-20 deg.C for testing. When the oral administration is carried out, the mouth of the dog is opened, and the prepared paclitaxel capsule is put into the pharynx for administration; collecting blood of 0.6mL in forelimb or hindlimb vein after 10mins, 30mins, 45mins, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h and 48h after administration, collecting blood plasma by heparin sodium anticoagulation centrifugation, and preserving at-20 ℃ for testing. The intravenous injection is paclitaxel injection (trade name taxol).
The test results are shown in table 1.
TABLE 1 in vivo bioavailability assay results for oral paclitaxel capsules
Dosage forms for administration Tmax(h) Cmax(ng/mL) F(％)
Example 1 0.72 4021 39.6
Example 2 0.71 3885 37.2
Example 3 0.72 3923 38.0
Example 4 0.70 3665 35.9
Example 5 0.70 3728 36.2
Example 6 0.70 3690 36.1
Example 7 0.69 3451 33.4
Example 8 0.68 3324 32.5
Example 9 0.69 3255 31.3
Comparative example 1 0.65 2689 24.7
Comparative example 2 0.70 2585 23.6
Comparative example 3 0.69 2732 25.0
Comparative example 4 0.71 61 0.4

Claims (10)

1. An oral paclitaxel capsule is prepared by dispersing amphiphilic polymer as carrier in oil phase, filling into soft capsule, and coating enteric coating.
2. The oral paclitaxel capsule according to claim 1, wherein the hydrophilic end of the amphiphilic polymer is methoxypolyethylene glycol and the hydrophobic end is polylactide.
3. The oral paclitaxel capsule according to claim 1, wherein the amphiphilic block polymer has a molecular weight of 5000 to 12000 daltons.
4. The oral paclitaxel capsule according to claim 2, wherein the total weight of the hydrophilic methoxy-terminated polyethylene glycol is 20-70% of the amphiphilic polymer.
5. The orally administrable paclitaxel capsule according to claim 1, wherein the oil phase is one or more of medium chain triglycerides, polyglycolyzed glycerides of oleic acid, glyceryl monolinoleate, and glyceryl monooleate.
6. The orally administrable paclitaxel capsule according to claim 1, wherein the weight ratio of paclitaxel to amphiphilic polymer is 1: 5 to 7.
7. The orally administrable paclitaxel capsule according to claim 1, wherein the weight ratio of paclitaxel to oil phase is 1: 30-70 parts.
8. The orally administrable paclitaxel capsule according to claim 1, wherein the weight ratio of paclitaxel to oil phase is 1: 40 to 50.
9. A method of preparing a paclitaxel capsule for oral administration according to any of claims 1 to 8, comprising the steps of:
a) weighing paclitaxel, amphiphilic polymer and oil phase in the formula amount in an organic solvent, and fully mixing by vortex to obtain a homogeneous solution;
b) rotary evaporation to remove organic solvent;
c) loading the prepared composite system into soft capsules;
d) the soft capsule is coated with enteric coating.
10. The method of claim 9, wherein the organic solvent is selected from the group consisting of acetonitrile, methanol, acetone, chloroform, and ethyl acetate.
CN202010999346.2A 2020-09-22 2020-09-22 Oral paclitaxel capsule Pending CN114246840A (en)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070196416A1 (en) * 2006-01-18 2007-08-23 Quest Pharmaceutical Services Pharmaceutical compositions with enhanced stability
US20110224151A1 (en) * 2008-11-21 2011-09-15 Samyang Corporation Polymeric Micelle Composition for Treatment of Resistant Cancer and Preparation Method of the Same
CN102836140A (en) * 2011-06-22 2012-12-26 鲁南制药集团股份有限公司 Arctigenin micro-emulsion enteric soft capsule preparation
KR101612259B1 (en) * 2015-07-30 2016-04-20 대화제약 주식회사 Pharmaceutical composition for oral administration comprising taxanes in high concentration
US20190000792A1 (en) * 2015-07-30 2019-01-03 Dae Hwa Pharma. Co., Ltd. Pharmaceutical composition for oral administration comprising high concentration taxane
US20200054628A1 (en) * 2016-10-20 2020-02-20 Pfizer Inc. Therapeutic Polymeric Nanoparticles Comprising Lipids and Methods of Making and Using Same

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070196416A1 (en) * 2006-01-18 2007-08-23 Quest Pharmaceutical Services Pharmaceutical compositions with enhanced stability
US20110224151A1 (en) * 2008-11-21 2011-09-15 Samyang Corporation Polymeric Micelle Composition for Treatment of Resistant Cancer and Preparation Method of the Same
CN102836140A (en) * 2011-06-22 2012-12-26 鲁南制药集团股份有限公司 Arctigenin micro-emulsion enteric soft capsule preparation
KR101612259B1 (en) * 2015-07-30 2016-04-20 대화제약 주식회사 Pharmaceutical composition for oral administration comprising taxanes in high concentration
US20190000792A1 (en) * 2015-07-30 2019-01-03 Dae Hwa Pharma. Co., Ltd. Pharmaceutical composition for oral administration comprising high concentration taxane
US20200054628A1 (en) * 2016-10-20 2020-02-20 Pfizer Inc. Therapeutic Polymeric Nanoparticles Comprising Lipids and Methods of Making and Using Same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
李国锋，等: "Labrasol 对紫杉醇经大鼠小肠定位吸收的影响", 《中国药学杂志》, vol. 44, no. 16, 31 August 2009 (2009-08-31), pages 1255 - 1258 *

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