WO2008110035A1 - Composition pharmaceutique contenant un complexe d'inclusion de cyclodextrine et de l'adefovir dipivoxil, et son procédé de préparation - Google Patents

Composition pharmaceutique contenant un complexe d'inclusion de cyclodextrine et de l'adefovir dipivoxil, et son procédé de préparation Download PDF

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WO2008110035A1
WO2008110035A1 PCT/CN2007/000816 CN2007000816W WO2008110035A1 WO 2008110035 A1 WO2008110035 A1 WO 2008110035A1 CN 2007000816 W CN2007000816 W CN 2007000816W WO 2008110035 A1 WO2008110035 A1 WO 2008110035A1
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Prior art keywords
cyclodextrin
adefovir dipivoxil
pharmaceutical composition
parts
adefovir
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PCT/CN2007/000816
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English (en)
Chinese (zh)
Inventor
Yong Ren
Jianfeng Gao
Binbin Han
Xueqin Ma
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Nanjing Normal University
Nanjing J. One Medical Technology Development Co., Ltd
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Priority to PCT/CN2007/000816 priority Critical patent/WO2008110035A1/fr
Publication of WO2008110035A1 publication Critical patent/WO2008110035A1/fr

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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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to a pharmaceutical composition comprising adefovir dipivoxil cyclodextrin inclusion complex and a process for the preparation thereof.
  • Adefovir dipivoxil trade name aganidine, chemical name 9-[2-[bis(pivaloyloxymethoxy)phosphorylmethoxy]ethyl]adenine, molecular formula C 2 ( ) H 32 N 5 0 8 P , molecular weight 501.47, said usual adult dose is 10mg, once daily.
  • This product is a prodrug modified by the ester structure of adenine phosphate compound adefovir. It can be rapidly hydrolyzed into adefovir after oral administration to exert antiviral effect.
  • Adefovir has broad-spectrum antiviral activity against hepatic DNA virus, retrovirus and herpes virus in vitro. Its active metabolite in the cell is adefovir diphosphate, which selectively inhibits HBV DNA polymerase.
  • adefovir has antiviral activity against primary HBV and transformed hepatic blastoma cell lines against HBV, duck hepatitis B virus (DHBV) and woodchuck hepatitis virus (WHV).
  • DHBV duck hepatitis B virus
  • WHV woodchuck hepatitis virus
  • adefovir inhibited viral DNA synthesis with IC 5 o values of 0.2 to 1.2 ⁇ M.
  • adefovir can promote the regeneration and renewal of hepatocytes and inhibit the replication of WHV.
  • adefovir dipivoxil was active against common types of lamivudine-resistant HBV, famciclovir-related mutations, and hepatitis B immunoglobulin deletion mutations.
  • Adefovir is poorly absorbed in the intestine after oral administration due to the negative charge of adefovir.
  • the adefovir dipivoxil is rapidly converted to adefovir after oral administration.
  • Oral adefovir dipivoxil 10 mg was used to recover 45% of adefovir from the urine for 24 h.
  • Cyclodextrin is a new class of pharmaceutical excipients that enhance drug stability, improve solubility, improve bioavailability, and reduce drug side effects.
  • cyclodextrin has a special structure that catalyzes ester hydrolysis (Organic Chemistry, 2002, 22(11): 827-834), which is an excellent catalyst for the hydrolysis of ester compounds, therefore, the use of cyclodextrin to improve the stability of the ester prodrug adefovir dipivoxil is technically particularly difficult.
  • ⁇ -cyclodextrin derivatives that can be used for injection also need to strictly control the residual amount of ⁇ -cyclodextrin.
  • Hydroxypropyl for injection The residual ⁇ -cyclodextrin in the bp- ⁇ -cyclodextrin should not be higher than 1.5% of the hydroxypropyl ⁇ -cyclodextrin content (Hydroxypropylbetadex, EUROPEAN PHARMACOPOEIA 4.6, ⁇ 4036-4037).
  • the valuable cyclodextrin-adefovir dipivoxil system and its technology should be mainly embodied in: to ensure that the ester prodrug has sufficient chemical stability and pharmacy stability and stability under the premise of ensuring no safety.
  • cyclodextrin excipients there are currently three cyclodextrin excipients in the clinic: ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin can be injected (Expert Opin Drug Deliv, 2005 Mar; 2 (2): 335-51).
  • Oral cyclodextrin and cyclodextrin derivatives include ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin.
  • an inclusion compound in preparing a cyclodextrin inclusion complex of adefovir dipivoxil, an inclusion compound can be prepared without using an organic solvent at all, and the obtained inclusion compound is a binary system of a drug-cyclodextrin.
  • the ⁇ -cyclodextrin inclusion compound can be used for oral administration, and the inclusion complex of other types of cyclodextrin has lower biological side effects than the inclusion complex prepared by ⁇ -cyclodextrin, and thus can be used for oral and injectable use. . This has great use value in the industry.
  • the present invention improves the adefovir dipivoxil formulation by using sulfobutyl- ⁇ -cyclodextrin or hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin (mass ratio 1:2:100), and the obtained low-fabrication
  • the ratio of 1:10 (mass ratio) inclusion compound can make adefovir dipivoxil solubility up to 93mg/ml, and the solid inclusion compound can be stably stored for more than 12 hours after being diluted by more than 500 times, in the presence of selected cyclodextrin.
  • Adefovir dipivoxil is chemically stable, not only has no hydrolytic decomposition phenomenon, but also has surprisingly enhanced stability.
  • the inclusion compound has high pharmacological stability and low irritation, and is suitable for various preparation dosage forms, and has important application value. Summary of the invention
  • One of the objects of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising adefovir dipivoxil cyclodextrin inclusion compound, which comprises acyclovir disintegration using cyclodextrin to obtain a clathrate having good stability of the main drug.
  • the pharmaceutical composition prepared from the inclusion compound can improve the solubility of adefovir dipivoxil, increase stability, reduce side effects, and obtain a new formulation of adefovir dipivoxil with clinical application value.
  • Another object of the present invention is to provide a process for the preparation of the above pharmaceutical composition.
  • the pharmaceutical composition of the present invention achieves the further improvement of the pharmacological properties of adefovir dipivoxil and the convenience of clinical application by the addition of cyclodextrin and optionally other pharmaceutical excipients.
  • the present invention provides a pharmaceutical composition comprising an adefovir dipivoxil cyclodextrin inclusion compound, the basic composition of which comprises:
  • the pharmaceutically acceptable cyclodextrin is one or more of ⁇ -cyclodextrin ( ⁇ -CD) or a derivative thereof, preferably one or more of substituted ⁇ -cyclodextrin, More preferably, it is one or more of sulfobutyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin.
  • the molecular weight of ⁇ -cyclodextrin is 1135; hydroxypropyl- ⁇ -cyclodextrin, sulfobutyl- ⁇ -cyclodextrin and hydroxypropyl-sulfobutyl group
  • the average molecular weight of ⁇ -cyclodextrin is: 1297 ⁇ 1744, 2089 ⁇ 2264 and 1353 ⁇ 2625, the mass ratio of adefovir dipivoxil to cyclodextrin 1:1 molecular inclusion ratio according to the molecular weight of different cyclodextrin , the ratio range is: 1 : 2.26 - 1 : 5.23.
  • the mass ratio of adefovir dipivoxil to cyclodextrin is from 1:2 to 1:100, preferably from 1:3 to 1:50.
  • the molecular inclusion ratio of adefovir dipivoxil to cyclodextrin is 1:1 to 1:5, meaning: in the inclusion complex system
  • adefovir dipivoxil and a cyclodextrin as a host molecule have a molecular ratio of 1:1 to 1:5.
  • it is 1:1 to 1:3.
  • the clathrate of the present invention is an inclusion complex prepared by the inclusion process using adefovir dipivoxil as a guest molecule and a cyclodextrin as a host molecule.
  • a cyclodextrin containing a plurality of host molecules may contain a guest molecule of adefovir dipivoxil, or a cyclodextrin of one host molecule may contain a guest molecule of adefovir.
  • cyclodextrin has various uses, in many cases, a pharmaceutical composition composed of a clathrate is used in an excess amount of cyclodextrin, and an excess of cyclodextrin added is used as an excipient, a stabilizer, a deodorant, and a filler.
  • a solubilizing agent to further improve the pharmaceutical properties of adefovir dipivoxil and to meet the technical requirements of various dosage forms in a few cases, it is also possible to use a cyclodextrin of less than 1:1 molecular ratio, in which case the drug is mainly In the form of a clathrate, the present invention uses a cyclodextrin ( ⁇ -cyclodextrin) having a minimum mass ratio of 1:2, and its drug/cyclodextrin molecular ratio is 1:0.884, although the cyclodextrin is slightly insufficient, The ⁇ -cyclodextrin inclusion adefovir dipivoxil has a large inclusion constant, and the drug is still mainly in the form of inclusion complex.
  • a portion of the excess cyclodextrin which is usually added is partially present in admixture with the clathrate in free form.
  • the partially free form of the cyclodextrin may be removed by a known method, for example, using a solvent having different solubility properties, in the case of pharmacy application, in most cases,
  • the unblended free cyclodextrin is present in admixture with the clathrate and is used directly to prepare a pharmaceutical composition without removal to prepare a pharmaceutical composition for oral or parenteral administration.
  • the invention also provides a novel preparation method of the pharmaceutical composition of the invention, which comprises preparing an adefovir dipivoxil cyclodextrin inclusion compound, and the preparation of the adefovir dipivoxil cyclodextrin inclusion compound comprises The following steps - a) taking adefovir dipivoxil and cyclodextrin;
  • the acid or base adjustment pH may be adjusted to slightly acidic or alkali to slightly alkaline by acid addition.
  • the resulting clathrates can be used in the preparation of pharmaceutical compositions or formulations for oral administration or for injection.
  • Adefovir dipivoxil has poor water solubility and strong lipophilicity. After mixing with cyclodextrin in aqueous solution, the hydrophobic cavity of cyclodextrin (inner diameter 7.84A ⁇ 9.07A) has enough space to accommodate lipophilic Ade.
  • Fuvirate molecule (4.25 ⁇ 6.54A) adefovir dipivoxil enters the cyclodextrin cavity and excludes the inclusion water in the cavity (up to 10 ⁇ 12 molecules of water), thus forming a stable inclusion complex, molecular package Stabilization after the combination, reducing the possibility of external interference, so that the molecular stability of adefovir dipivoxil is enhanced; because cyclodextrin has higher water solubility than adefovir dipivoxil, the adduct state of Ade The solubility of foswell ester is also improved.
  • the clathrate of the present invention has sufficient stability, and the inclusion stability constant of different cyclodextrins is Ka g SM ⁇ SSM' 1 .
  • the solid inclusion compound prepared by the invention has high water solubility and is easy to dissolve without adding other auxiliary solvents, and the prepared aqueous solution has small side effects of hemolysis and is suitable for clinical use.
  • the solid inclusion compound containing clinical dose of 20 mg of adefovir dipivoxil can be kept stable within 10 to 500 times of dilution with water for injection.
  • the solid inclusion compound can be diluted for 10 to 500 times to reach a suitable concentration for clinical injection.
  • the above-obtained clathrate can be optionally formulated into a pharmaceutical composition of various dosage forms in a desired formulation with a pharmaceutical excipient.
  • the pharmaceutical composition of the present invention includes various usual dosage forms, and for example, it may be an oral dosage form, an injection dosage form or the like.
  • the oral dosage forms include, but are not limited to, preparations such as tablets, capsules, granules, powders, sustained release tablets or dispersion tablets.
  • the dosage forms include, but are not limited to, freeze-dried powder injection, sterile powder injection, small-volume injection, and large-volume infusion.
  • the pharmaceutical composition of the present invention may optionally further comprise one or more of a pharmaceutically acceptable diluent, a disintegrant, a lubricant, a wetting agent, and a binder.
  • the content of adefovir dipivoxil in the pharmaceutical composition can be determined according to factors such as the dosage form, suitable population, and the like, and it is usually 0.2 to 33% by weight.
  • the amount of one or more of the above diluents, disintegrants, lubricants, wetting agents and binders is not Particularly limited, those skilled in the art can select as needed when preparing a particular dosage form.
  • the content of the diluent in the pharmaceutical composition is 0 to 80% by weight, preferably 10 to 50% by weight; the content of the disintegrant is 0 to 30% by weight, preferably less than 0.5% by weight; and the content of the lubricant is 0 to 10% by weight, preferably It is 0.3 ⁇ 1wt%; the content of wetting agent or binder is 0 ⁇ 5%.
  • adefovir dipivoxil is present in the form of a cyclodextrin inclusion compound.
  • the pharmaceutical carrier used in the preparation of the pharmaceutical composition of the present invention in an oral dosage form is not particularly limited, and it may be a usual carrier for oral use in the art, for example, the diluent may be selected from starch, ⁇ -cyclodextrin or a derivative thereof.
  • the disintegrant may be selected from the group consisting of starch and carboxy a plurality of one or any combination of sodium methyl starch, crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium or cross-linked polyvinylpyrrolidone; a plurality of one or any combination selected from the group consisting of magnesium stearate, stearic acid, sodium decyl sulfate, talc, PEG4000, PEG6000 or micronized silica; the wetting agent or binder is optional A plurality of one or any combination of water, ethanol, starch syrup, sodium carboxymethylcellulose, hydroxypropylmethylcellulose or dextrin.
  • the pharmaceutical composition of the present invention comprises, in parts by mass, 10 parts of adefovir dipivoxil, 20-500 parts of ⁇ -cyclodextrin or a derivative thereof, pregelatinization 30-300 parts of starch, 10-100 parts of microcrystalline cellulose, 2-50 parts of croscarmellose sodium, 0.5-10 parts of talc, 0.2-5 parts of magnesium stearate; wherein, adefovir The ester is in the form of a cyclodextrin inclusion compound.
  • Adefovir dipivoxil and ⁇ -cyclodextrin are prepared as a clathrate according to the aforementioned method, and the resulting clathrate is further prepared into an oral dosage form such as a tablet by a conventional method.
  • adefovir dipivoxil as a clathrate can achieve beneficial technical effects of enhancing drug stability, improving drug solubility, improving dissolution and enhancing activity.
  • the prepared oral preparation is significantly more stable under acidic conditions than the conventional preparation, which is advantageous for improving the oral bioavailability of adefovir.
  • the injection dosage form may be prepared by using the solid inclusion compound after sterilization treatment, or may be prepared by using the liquid clathrate after sterilization treatment; or, 'the above solid inclusion compound or liquid inclusion compound may also be After sterilization, the preparation is sterilized by a suitable method before being dispensed into a glass bottle, for example, by filtration sterilization, or by a suitable method after the preparation is dispensed in a glass bottle, for example, autoclaving. Meanwhile, the cyclodextrin inclusion complex containing adefovir dipivoxil of the present invention, which is further prepared for injection, may be a solution type aqueous injection, and may be prepared, for example, by a common aqueous injection production process.
  • the present invention contains Ade
  • the cyclodextrin inclusion compound of foswell ester, the further prepared pharmaceutical composition for injection can be a solid powder injection, for example, a sterile aseptic powder injection can be prepared by a common aseptic dispensing process, or A freeze-dried powder injection can be prepared by a conventional freeze-drying process.
  • the pharmaceutical composition of the present invention may optionally further comprise one or more of a pharmaceutically acceptable isotonicity adjusting agent, a pH adjusting agent and a topical analgesic.
  • the pharmaceutically acceptable carrier to be used for the preparation of the injectable pharmaceutical composition of the present invention is not particularly limited, and it may be a pharmaceutically acceptable carrier for injection for use which is generally used in the art.
  • Isotonicity adjusting agents in the carrier include, but are not limited to, glucose, sodium chloride, mannitol, lactose, dextran, fructose or glycerol; pH adjusting agents include, but are not limited to, hydrochloric acid, sulfuric acid, citric acid, sodium hydroxide , disodium hydrogen phosphate or sodium dihydrogen phosphate; local analgesics, including but not limited to benzyl alcohol, chlorobutanol, procaine hydrochloride or lidocaine hydrochloride.
  • the glucose, mannitol or dextran and the like also have an osmotic pressure regulating effect.
  • the content of adefovir dipivoxil in the pharmaceutical composition for injection can be determined according to factors such as the dosage form and the suitable population, and is usually 0.05 to 33% by weight.
  • the amount of the above isotonicity adjusting agent, pH adjusting agent and topical analgesic agent is not particularly limited, and those skilled in the art can select them as needed in preparing a specific dosage form.
  • the content of the isotonicity adjusting agent in the pharmaceutical composition is 0 to 20% by weight, preferably 0 to 5% by weight; the content of the pH adjusting agent can be determined according to the pH of the final product, preferably the pH is adjusted to the physiological pH range; the content of the local analgesic agent It is 0 to 3 wt% ; the amount of water for injection as a solvent is well known in the art.
  • adefovir dipivoxil is present in the form of a cyclodextrin inclusion compound.
  • a specific embodiment of the pharmaceutical composition comprises: a portion of adefovir dipivoxil, 20 to 500 parts of ⁇ -cyclodextrin or a derivative thereof, and 0 200 parts of sodium chloride. , 0 ⁇ 500 parts of glucose, 0 ⁇ 2000 parts of lactose, 0 ⁇ 2000 parts of mannitol, and 2000 ⁇ 20000 parts of water for injection; wherein the water for injection can be present in the final pharmaceutical composition, or from the final Removal in the pharmaceutical composition; the adefovir dipivoxil is present in the form of a cyclodextrin inclusion complex.
  • the above-mentioned water for injection is present in the final pharmaceutical composition; as a lyophilized powder injection, the above-mentioned water for injection is removed from the final pharmaceutical composition.
  • the adefovir dipivoxil cyclodextrin inclusion compound of the invention obviously increases the solubility of adefovir dipivoxil, the stability of adefovir dipivoxil is significantly enhanced, the hemolysis effect is reduced, and it is suitable for development into various injection preparations.
  • the method of the invention can prepare the inclusion compound under pure water condition, thereby avoiding the residue of the organic solvent and ensuring the safety of administration.
  • the preparation method of the inclusion compound is simple, simple in operation, easy to control, and free from pollution.
  • the inclusion complex is stable in nature and has good compatibility with pharmaceutical excipients, and the inclusion compound is easy to process.
  • Figure 1 shows the UV absorption of the sulfobutyl- ⁇ -cyclodextrin/adefovir dipivoxil and the UV absorption of adefovir dipivoxil at different concentrations of sulfobutyl- ⁇ -cyclodextrin.
  • a good linear relationship was obtained by plotting 1//L4 vs. 1/[sulfobutyl- ⁇ -cyclodextrin], and the linear regression was obtained by the intercept/slope of the adefovir dipivoxil/cyclodextrin inclusion constant.
  • Figure 2 is a differential thermal analysis of the sample, as shown (top to bottom sample: adefovir dipivoxil; ⁇ -cyclodextrin; a mixture of adefovir dipivoxil and ⁇ -cyclodextrin; adefovir Ester/ ⁇ -cyclodextrin inclusion complex), adefovir dipivoxil curve: 104 ° C is the melting point of adefovir dipivoxil, nearly 210 ⁇ is the decomposition peak; cyclodextrin: 70-90 ⁇ dehydration endothermic peak, nearly 300 ⁇ Start decomposition; physical mixture: maintains the characteristic peaks of cyclodextrin and adefovir dipivoxil, which is basically the superposition of each compound; inclusion complex map: melting point characteristic curve of adefovir dipivoxil and dehydration endothermic peak of cyclodextrin It disappears and decomposes after 300 °
  • Figure 3 is an HPLC diagram of the adefovir dipivoxil feedstock. As shown, the retention time of adefovir dipivoxil is
  • Figure 4 is a HPLC diagram of adefovir dipivoxil. As shown, the adefovir dipivoxil feedstock after 8 hours of acid destruction, the sample retention time was 15.748 minutes, and the adefovir dipivoxil content was significantly reduced to 50.22%.
  • Example 3 It was substantially the same as in Example 1, except that 26 g of hydroxypropyl- ⁇ -cyclodextrin was substituted for ⁇ -cyclodextrin; it was prepared in 30 ml of purified water, and dried under reduced pressure without filtration to obtain a solid clathrate.
  • Example 3
  • Example 4 It was substantially the same as in Example 1, except that 42 g of sulfobutyl- ⁇ -cyclodextrin was substituted for ⁇ -cyclodextrin; it was prepared in 45 ml of purified water, and dried under reduced pressure without filtration to obtain a solid clathrate.
  • Example 4
  • Example 5 Basically the same as in Example 1. except that 27 g of hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin was used in 30 ml of purified water, and dried under reduced pressure without filtration to obtain a solid clathrate. 'Example 5:
  • Example 2 Basically the same as in Example 1, except that 5 g of ⁇ -cyclodextrin was mixed with 50 ml of pure water to heat
  • Example 6 1.0 g of adefovir dipivoxil was added at a temperature of 50 ° C, and after 1 hour of incubation, it was directly dried under reduced pressure to obtain a solid clathrate.
  • Example 6 1.0 g of adefovir dipivoxil was added at a temperature of 50 ° C, and after 1 hour of incubation, it was directly dried under reduced pressure to obtain a solid clathrate.
  • Example 7 Basically the same as in Example 5, except that hydroxypropyl- ⁇ -cyclodextrin was substituted for ⁇ -cyclodextrin.
  • Example 8 Basically the same as in Example 5, except that sulfobutyl- ⁇ -cyclodextrin was substituted for ⁇ -cyclodextrin.
  • Example 8 sulfobutyl- ⁇ -cyclodextrin was substituted for ⁇ -cyclodextrin.
  • Example 9 Basically the same as in Example 5, except that the ⁇ -cyclodextrin was replaced with a 1:1 mixed cyclodextrin of hydroxypropyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin.
  • Example 12 Basically the same as in Example 9, except that sulfobutyl- ⁇ -cyclodextrin was substituted for ⁇ -cyclodextrin.
  • Example 12 sulfobutyl- ⁇ -cyclodextrin was substituted for ⁇ -cyclodextrin.
  • Example 13 Basically the same as in Example 9, except that hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin was substituted for ⁇ -cyclodextrin.
  • Example 14 Basically the same as in Example 9, except that the cyclodextrin was replaced with a cyclodextrin having a mass ratio of hydroxypropyl- ⁇ -cyclodextrin to ⁇ -cyclodextrin of 1:9.
  • Example 14 Basically the same as in Example 9, except that the cyclodextrin was replaced with a cyclodextrin having a mass ratio of hydroxypropyl- ⁇ -cyclodextrin to ⁇ -cyclodextrin of 1:9.
  • Example 15 Basically the same as in Example 9, except that a cyclodextrin having a mass ratio of sulfobutyl- ⁇ -cyclodextrin to ⁇ -cyclodextrin of 1:10 was used instead of ⁇ -cyclodextrin.
  • a cyclodextrin having a mass ratio of sulfobutyl- ⁇ -cyclodextrin to ⁇ -cyclodextrin of 1:10 was used instead of ⁇ -cyclodextrin.
  • Example 16 Basically the same as in Example 9, except that the cyclodextrin was replaced with a mixed cyclodextrin having a mass ratio of hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin to ⁇ -cyclodextrin of 1:20. + Example 16:
  • Example 17 The procedure was basically the same as in Example 9, except that a mixed cyclodextrin having a mass ratio of hydroxypropyl- ⁇ -cyclodextrin to sulfobutyl- ⁇ -cyclodextrin of 5:1 was used instead of ⁇ -cyclodextrin.
  • a mixed cyclodextrin having a mass ratio of hydroxypropyl- ⁇ -cyclodextrin to sulfobutyl- ⁇ -cyclodextrin of 5:1 was used instead of ⁇ -cyclodextrin.
  • Example 18 The procedure was basically the same as in Example 9, except that a cyclodextrin having a mass ratio of hydroxypropyl- ⁇ -cyclodextrin to sulfobutyl- ⁇ -cyclodextrin of 50:1 was used instead of ⁇ -cyclodextrin. - Example 18:
  • Example 19 Basically the same as in Example 9, except that the ⁇ -cyclodextrin was replaced with a mixed cyclodextrin having a mass ratio of hydroxypropyl- ⁇ -cyclodextrin to sulfobutyl- ⁇ -cyclodextrin of 1:100.
  • Example 19 Basically the same as in Example 9, except that the ⁇ -cyclodextrin was replaced with a mixed cyclodextrin having a mass ratio of hydroxypropyl- ⁇ -cyclodextrin to sulfobutyl- ⁇ -cyclodextrin of 1:100.
  • Example 20 The procedure was basically the same as in Example 9, except that the cyclodextrin was substituted with ⁇ -cyclodextrin with a hydroxypropyl- ⁇ -cyclodextrin and a hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin mass ratio of 1:1.
  • Example 20 The procedure was basically the same as in Example 9, except that the cyclodextrin was substituted with ⁇ -cyclodextrin with a hydroxypropyl- ⁇ -cyclodextrin and a hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin mass ratio of 1:1.
  • Example 9 Basically the same as in Example 9, except that the cyclodextrin was replaced with a mixed cyclodextrin having a mass ratio of 1:1 of sulfobutyl- ⁇ -cyclodextrin to hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin.
  • Example 23 10 g of the clathrate prepared in Example 21 was added, 80 g of microcrystalline cellulose and 10 g of silica were added, and the mixture was uniformly mixed and directly placed in a pharmaceutical aluminum foil pouch so that each pouch was equivalent to 10 mg of adefovir dipivoxil.
  • the pharmaceutical composition of the present invention is obtained.
  • Example 21 Preparation of inclusion complex, the addition of microcrystalline cellulose 30g starch 20g, 30 g, magnesium stearate lg, thoroughly mixed, and sodium carboxymethyl starch are hook, the drug directly into the foil bag, so that each bag It is equivalent to 10 mg of adefovir dipivoxil.
  • the pharmaceutical composition of the present invention is obtained.
  • Example 25 Take 84.2 g of the clathrate prepared in Example 21, add 10 g of microcrystalline cellulose, 0.5 g of sodium carboxymethyl starch, granulate with 5% starch slurry, dry, add 0.3 g of magnesium stearate, and mix well. The 18 mesh sieve was granulated and compressed to make each tablet equivalent to 10 mg of adefovir.
  • the pharmaceutical composition of the present invention is obtained.
  • Example 27 Take 1.2 g of the clathrate of Example 25, dissolve in 70 ml of water, add 5 g of sodium chloride, stir to dissolve, add water for injection to 100 ml, and adjust the pH to 6.6 7.0 with 1N hydrochloric acid or 1N sodium hydroxide. The bacteria were filtered, and the drug solution was dispensed in a 5 ml ampoule to obtain the pharmaceutical composition of the present invention.
  • Example 27 Example 27:
  • Example 28 60 g of the clathrate of Example 25 was added, 30 g of pregelatinized starch, 10 g of microcrystalline cellulose, 2 g of croscarmellose sodium, 0.5 g of talc and 0.2 g of magnesium stearate were added, and the mixture was uniformly mixed. Capsules, each serving equivalent to 10 mg of adefovir dipivoxil. The pharmaceutical composition of the present invention is obtained.
  • Example 28 60 g of the clathrate of Example 25 was added, 30 g of pregelatinized starch, 10 g of microcrystalline cellulose, 2 g of croscarmellose sodium, 0.5 g of talc and 0.2 g of magnesium stearate were added, and the mixture was uniformly mixed. Capsules, each serving equivalent to 10 mg of adefovir dipivoxil. The pharmaceutical composition of the present invention is obtained.
  • Example 28 60 g of the clathrate of Example 25 was added, 30 g of pre
  • Example 29 60 g of the clathrate of Example 25 was added, 300 g of pregelatinized starch, 100 g of microcrystalline cellulose, 50 g of croscarmellose sodium, 10 g of talc and 5 g of magnesium stearate were mixed well, and the capsule was directly filled. , each capsule is equivalent to 10mg containing adefovir.
  • the pharmaceutical composition of the present invention is obtained.
  • Example 30 60 g of the clathrate of Example 25 was dissolved in 5000 ml of water for injection, aseptically filtered, and the drug solution was dispensed into a 5 ml ampoule to obtain the pharmaceutical composition of the present invention.
  • Example 30 60 g of the clathrate of Example 25 was dissolved in 5000 ml of water for injection, aseptically filtered, and the drug solution was dispensed into a 5 ml ampoule to obtain the pharmaceutical composition of the present invention.
  • Example 30 60 g of the clathrate of Example 25 was dissolved in 5000 ml of water for injection, aseptically filtered, and the drug solution was dispensed into a 5 ml ampoule to obtain the pharmaceutical composition of the present invention.
  • Example 30 60 g of the clathrate of Example 25 was dissolved in 5000 ml of water for injection, aseptically filtered, and the drug solution was dispensed into a 5 ml ampoule to obtain the pharmaceutical composition of
  • Example 31 60 g of the clathrate of Example 25 was added, and 15000 ml of water for injection was dissolved, and 200 g of sodium chloride, 500 g of glucose, 2000 g of lactose and 2000 g of mannitol were added, stirred and dissolved, and sterilely filtered, and the drug solution was dispensed into a 20 ml ampoule. That is, the pharmaceutical composition of the present invention is obtained.
  • Example 31 60 g of the clathrate of Example 25 was added, and 15000 ml of water for injection was dissolved, and 200 g of sodium chloride, 500 g of glucose, 2000 g of lactose and 2000 g of mannitol were added, stirred and dissolved, and sterilely filtered, and the drug solution was dispensed into a 20 ml ampoule. That is, the pharmaceutical composition of the present invention is obtained.
  • Example 31 60 g of the clathrate of Example 25 was added, and 15000 m
  • Example 33 Take 110g of the clathrate of Example 31, add 1500ml of water to dissolve, add 2g of sodium chloride, stir to dissolve, add water for injection to 2000ml, sterile filtration, and dispense the liquid in 2ml ampoules, the invention Pharmaceutical composition.
  • Example 33 Take 110g of the clathrate of Example 31, add 1500ml of water to dissolve, add 2g of sodium chloride, stir to dissolve, add water for injection to 2000ml, sterile filtration, and dispense the liquid in 2ml ampoules, the invention Pharmaceutical composition.
  • Example 33 Take 110g of the clathrate of Example 31, add 1500ml of water to dissolve, add 2g of sodium chloride, stir to dissolve, add water for injection to 2000ml, sterile filtration, and dispense the liquid in 2ml ampoules, the invention Pharmaceutical composition.
  • Example 33 Take 110g of the clathrate of Example 31, add 1500ml of water to dissolve, add 2g of sodium chloride, stir to dissolve, add water for injection to 2000
  • Example 34 A solution of 500 g of hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin and 2000 ml of water was mixed, 10 g of adefovir dipivoxil was added, and the mixture was heated to 60 ° C and stirred for 1 hour, and then stirred at room temperature for 1 hour, and allowed to stand at room temperature for 12 hours. Hour; freeze-drying, that is, an inclusion compound. 100 g of the clathrate was taken and directly encapsulated so that each of the tablets corresponded to a pharmaceutical composition containing adefovir dipivoxil.
  • Example 34 A solution of 500 g of hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin and 2000 ml of water was mixed, 10 g of adefovir dipivoxil was added, and the mixture was heated to 60 ° C and stirred for 1 hour, and then stirred at room temperature for 1 hour, and allowed to stand at room temperature for
  • Example 35 Take 51 g of the clathrate of Example 33, dissolve it in 800 ml of water, add 50 g of glucose, stir to dissolve, add water for injection to 1000 ml, sterilely filter, and dispense the liquid in a 10 ml ampoule, so that the invention is obtained.
  • the obtained solid inclusion compound was added in three portions, and physiological saline was added to prepare a solution of 2 ml: 10 mg, 10 ml: 10 mg, and 100 ml: 10 mg according to adefovir dipivoxil, and separately dispensed into 2 ml, 10 ml, and 100 ml, and sterilized. That is, a pharmaceutical composition of a solution-type injection containing 10 mg of adefovir dipivoxil per bottle was prepared.
  • Example 36 Example 36:
  • Example 35 Take the appropriate amount of the clathrate prepared in Example 35, prepare the solution according to the ratio shown in Table 1, and dispense it into a glass bottle. Then, the solution is freeze-dried according to the preparation process of the freeze-dried powder injection.
  • Adefovir A pharmaceutical composition of the powder dosage form of 10 mg of ester.
  • a suitable concentration of adefovir dipivoxil solution was prepared in pH 6.86 phosphate buffer for full wavelength scanning to select the appropriate assay wavelength.
  • UV absorption values of the 1:1 molar ratio solution differed the most, indicating that the inclusion ratio of adefovir dipivoxil/P-CD was 1:1.
  • a dilute solution of adefovir dipivoxil was prepared using ⁇ 6.86 mixed phosphate buffer, and then a cyclodextrin solution was prepared using the diluted solution.
  • a certain volume of adefovir dipivoxil solution was UV-scanned to obtain a specific 262 nm UV absorption (A 0 ), and the cyclodextrin concentration was changed to 1.75 ⁇ l ⁇ r 4 -3.48 ⁇ l (r 4 mol/L, different cyclodextrin concentrations were obtained).
  • the inclusion constant Ka of adefovir dipivoxil/cyclodextrin can be obtained from the intercept/slope of the formula.
  • Experiments verify the inclusion constants of ⁇ -cyclodextrin/adefovirvirtide, hydroxypropyl- ⁇ -cyclodextrin/adefovirvirtide and sulfobutyl- ⁇ -cyclodextrin/adefovir .
  • the inclusion constant of adefovir dipivoxil and cyclodextrin is Ka: 976 ⁇ - 1 -7752 ⁇ 1 , which proves that adefovir dipivoxil and cyclodextrin are sufficiently stable.
  • the inclusion UV scan of sulfobutyl- ⁇ -cyclodextrin/adefovirvirtide is shown in Figure 1.
  • adefovir dipivoxil has a peak at 90 °C, which is a desorption endothermic peak. There are some characteristic peaks at around 200 ,, which are melting decomposition peaks; cyclodextrin also has 70-90 ⁇ and 300-330 ⁇ .
  • One peak is a dehydration endothermic peak and a melting decomposition peak.
  • the physical mixture maintains the endothermic peak of cyclodextrin and adefovir dipivoxil, which is basically a superposition of each compound, and on the map of the clathrate, the position (temperature) and shape (thermal effect) of each peak occur. The change, speculated that the inclusion complex has formed.
  • the differential thermal analysis chart is shown in Figure 2.
  • Experimental Example 4 Nuclear Magnetic Resonance Analysis
  • Adefovir dipivoxil starting material and adefovir dipivoxil / sulfobutyl- ⁇ -cyclodextrin inclusion complex (adefovir dipivoxil: cyclodextrin The mass ratio is 1: 10). It is dissolved in the mobile phase. After sonication for 30 minutes, it is allowed to stand at 0, 24, respectively.
  • adefovir dipivoxil starting material Take adefovir dipivoxil starting material and adefovir dipivoxil / sulfobutyl- ⁇ -cyclodextrin inclusion complex (adefovir dipivoxil: cyclodextrin mass ratio 1: 10), divided into three parts for the test Samples, respectively, the light test, high temperature test and high humidity test specific methods:
  • adefovir dipivoxil starting material Take adefovir dipivoxil starting material and adefovir dipivoxil / sulfobutyl- ⁇ -cyclodextrin (adefovir dipivoxil: cyclodextrin mass ratio 1: 10), respectively, add 5 ml of pH1. , still, sample every 4 hours, take appropriate The amount of alkali is neutralized, diluted, injected, and calculated.
  • adefovir dipivoxil starting material Take adefovir dipivoxil starting material and adefovir dipivoxil / sulfobutyl- ⁇ -cyclodextrin (adefovir dipivoxil: cyclodextrin mass ratio 1: 10), add 5ml of phosphate buffer solution with pH 6.86 , stationary, sampling every 4 hours, dilution, injection, calculation.
  • the solid inclusion compound with a mass ratio of 1:20 is diluted 2 to 500 times with physiological saline and isotonic glucose solution respectively. After dilution, it is sterilized to prepare different concentrations of injection, and continuous observation for 5 hours to 10 days, among which Ade
  • the stability test results of the brine dilution system of the foswell ester/sulfobutyl- ⁇ -cyclodextrin inclusion compound are shown in Table 10. Table 10, formulation status under different dilution factors
  • adefovir dipivoxil sulfobutyl- ⁇ -cyclodextrin inclusion compound prepared by the method of the invention has low hemolytic property, especially under high concentration conditions, and has low irritation and safety, and is suitable for Injection administration; ⁇ -cyclodextrin inclusion compound is highly hemolytic and not suitable for injection, and ⁇ -cyclodextrin is strictly prohibited for injection use because of its high nephrotoxicity.
  • Experimental Example 12 Effect of organic solvents on adefovir dipivoxil inclusion complex
  • the adefovir dipivoxil is added to the inclusion compound prepared by the organic solvent to prepare the solution, and the preparation method comprises the following steps: preparing adefovir dipivoxil ethanol solution by dissolving 100 mg of adefovir dipivoxil in 1 ml of ethanol. 700mg ⁇ -cyclodextrin with 5 ml of pure water The mixture was mixed and slowly added to the cyclodextrin solution at 55 ° C, then stirred well for 1 hour, cooled, placed under 5 Torr for 1 day, filtered, and the solid was washed with a little cold ethanol. The mixture was thoroughly filtered and dried, and the solid was dried under reduced pressure to yield 610 mg.
  • 1 H NMR was measured by using D20 as a solvent, and the nuclear magnetic resonance spectrum is shown in Fig. 5.
  • the iHNMR spectrum of the adefovir dipivoxil starting material by comparative nuclear magnetic resonance is shown in Fig. 6.
  • the iHNMR spectrum of adefovir dipivoxil (Fig. 6) demonstrates that the peak area of the a, b protons (2 protons) of the aromatic ring in the adefovir dipivoxil molecule and the e protons of the six methyl groups in the molecule (18 protons) The peak area ratio is 1:9.
  • 1 H NMR spectrum (Fig. 6)
  • the inclusion compound prepared by ethanol solubilization contains the methyl peak of ethanol (ethanol under the same measurement conditions)
  • Defovirtide from the proton peak area of ⁇ -cyclodextrin C-1 in Figure 5 (representing 1 mole of cyclodextrin), it is proved that the inclusion complex prepared by ethanol solubilization is actually a ternary inclusion compound,
  • the composition is: adefovir dipivoxil-ethanol- ⁇ -cyclodextrin; its composition ratio is 1:2:2.

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Abstract

L'invention concerne une composition pharmaceutique contenant un complexe d'inclusion de cyclodextrine et de l'adéfovir dipivoxil, et son procédé de préparation. Cette composition comprend essentiellement de l'adéfovir dipivoxil et une cyclodextrine pharmaceutiquement acceptable choisie au moins parmi l'un des éléments du groupe comprenant la β-cyclodextrine et ses dérivés. La solubilité et la stabilité de l'adéfovir dipivoxil peut être accrue, et l'hémolyse peut être réduite en fonction de l'invention.
PCT/CN2007/000816 2007-03-14 2007-03-14 Composition pharmaceutique contenant un complexe d'inclusion de cyclodextrine et de l'adefovir dipivoxil, et son procédé de préparation WO2008110035A1 (fr)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
CN1615868A (zh) * 2004-09-29 2005-05-18 南京师范大学 盐酸哌唑嗪的环糊精包合物及其制备方法
CN1800221A (zh) * 2005-11-02 2006-07-12 南京师范大学 羟丙基－磺丁基－β－环糊精及其制备方法、分析方法以及在药学上的应用
CN1879635A (zh) * 2005-06-13 2006-12-20 博瑞生物医药技术(苏州)有限公司 阿德福韦酯的β－环糊精包合物及其制剂

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CN1615868A (zh) * 2004-09-29 2005-05-18 南京师范大学 盐酸哌唑嗪的环糊精包合物及其制备方法
CN1879635A (zh) * 2005-06-13 2006-12-20 博瑞生物医药技术(苏州)有限公司 阿德福韦酯的β－环糊精包合物及其制剂
CN1800221A (zh) * 2005-11-02 2006-07-12 南京师范大学 羟丙基－磺丁基－β－环糊精及其制备方法、分析方法以及在药学上的应用

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