WO2006066509A1 - Préparation microsphérique à libération prolongée injectable de dérivés de 3,3-diphénylpropylamine servant d'antagonistes du récepteur muscarinique - Google Patents

Préparation microsphérique à libération prolongée injectable de dérivés de 3,3-diphénylpropylamine servant d'antagonistes du récepteur muscarinique Download PDF

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Publication number
WO2006066509A1
WO2006066509A1 PCT/CN2005/002277 CN2005002277W WO2006066509A1 WO 2006066509 A1 WO2006066509 A1 WO 2006066509A1 CN 2005002277 W CN2005002277 W CN 2005002277W WO 2006066509 A1 WO2006066509 A1 WO 2006066509A1
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Prior art keywords
sustained release
microsphere preparation
hydroxy
phenylpropylamine
diisopropyl
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PCT/CN2005/002277
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English (en)
Chinese (zh)
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Youxin Li
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Youxin Li
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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder

Definitions

  • the present invention relates to a slow-drying t-ball preparation for injection of a 3,3-diphenylpropylamine derivative and a preparation method thereof, and to a preparation for the treatment or adjuvant treatment of a disease associated with muscarinic receptors.
  • Use of drugs with unstable or overactive bladder such as urgency or stress urinary incontinence, impulsive incontinence, urgency or frequent urination.
  • tolterodine ((R)-N, N-diisopropyl-3-(2-hydroxy-5-nonylphenyl)-3-phenylpropylamine) is a muscarinic receptor antagonist
  • the agent is converted into (R)-N,N-diiso-3-(2-hydroxy-5-hydroxydecylphenyl)-3-phenylpropylamine and 5 by the enzyme CYP2D6 in the liver after oral administration into the body.
  • Another prodrug of (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine, (R)-N, N-di Isobutyrate of isopropyl-3-(2-hydroxy-5-hydroxydecylphenyl)-3-phenylpropylamine is in clinical trials (EP1077912 and Inpharma 1 (2004) 7-7 (1)), The drug is orally absorbed and converted into (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine to produce pharmacological activity.
  • Clinical trial results show that the drug has a good muscarinic receptor antagonism, but its oral bioavailability is lower than tolterodine, and its absorption rate through the gastrointestinal tract is low.
  • 3-diphenylpropylamine muscarinic receptor antagonist the fluctuation of drug concentration in the blood, resulting in reduced efficacy, increased side effects, such as dry mouth, constipation, indigestion, headache, dizziness, dry eyes, Urinary retention.
  • the unabsorbed fraction will produce pre-systemic side effects or interactions (EP1077912), and the first-pass effect of the liver also leads to reduced efficacy, increased side effects, and (R) - N, N-diisopropyl-3-(2-hydroxyl -5-Hydroxyphenylphenyl)-3-phenylpropylamine has a low oral bioavailability and is not suitable for oral dosage forms.
  • 3,3-diphenylpropylamine muscarinic receptor antagonists can be administered by ordinary injection, but for patients, as a long-term treatment, one or more injections per day will obviously increase the patient's pain. And discomfort.
  • US6517864 reports a 24-hour transdermal formulation of tolterodine and (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine, although This dosage form can release the drug at a relatively stable rate, but its low bioavailability ( ⁇ 10%) leads to an increase in the cost of its treatment, and it cannot be sustained and sustained. Therefore, it still needs to be developed as a muscarinic receptor antagonist.
  • one aspect of the present invention relates to a sustained release microsphere preparation for injection of a 3,3-diphenylpropylamine derivative which is a 3,3-diphenylpropylamine derivative represented by the following formula (I) and a One or more biodegradable pharmaceutically acceptable polymeric excipients and optionally other pharmaceutically acceptable excipients.
  • Another aspect of the invention relates to a process for the preparation of a sustained release microsphere preparation for injection of the above 3,3-diphenylpropylamine derivative.
  • Still another aspect of the present invention relates to the above-mentioned 3, 3-diphenylpropylamine derivative microsphere preparation for injection for the treatment or adjuvant treatment of a muscarinic receptor-related disease and an unstable or overactive bladder such as urgency Or the use of drugs for stress urinary incontinence, impulsive incontinence, urgency or frequent urination.
  • sustained release microsphere preparation of the present invention is represented by the following formula (I) a 3,3-diphenylpropylamine derivative, its optical enantiomer or racemate, a prodrug or analog thereof or a pharmaceutically acceptable salt thereof, and one or more biodegradable pharmaceuticals Polymer excipients and optionally other pharmaceutically acceptable excipients:
  • R1 represents a hydrogen atom, ( ⁇ -( 6 alkanoyl or C 7 -C, aroyl;
  • R2 represents a hydrogen atom, D- C 6 alkyl, hydroxy or C "C 6 hydroxyalkyl
  • R3 and R4 each independently represent a hydrogen atom or -( 6 alkyl
  • R5 represents a hydrogen atom, a halogen, a CfC 6 alkyl group, a hydroxyalkyl group, a C, a C 6 alkoxy group.
  • aroyl as used in the present invention means an aroyl group containing a benzene ring or other aromatic group, for example, a benzoyl group or an optionally substituted benzoyl group, and the substituent is selected from a fluorenyl group or Alkoxy groups, etc.
  • the above 3, 3-diphenylpropylamine derivative is selected from the group consisting of the compounds (la), (11), (111), (IV), (V) having the specified substituents in Table 1 below. Or at least one of (VI) or a pharmaceutically acceptable acid addition salt thereof.
  • the 3,3-diphenylpropylamine derivative can be used in the form of a free base or an acid addition salt thereof.
  • the acid which forms the acid addition salt includes, but not limited to, hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, tartaric acid, fumaric acid, lactic acid or citric acid.
  • the medicinal polymeric excipients used in the sustained-release microsphere preparation of the present invention are various biodegradable but water-insoluble polymeric materials, including but not limited to polylactide-glycolide, polylactic acid, Polyglycolic acid, poly-3-hydroxybutyrate, polylactone, polyanhydride, polyhydroxybutyrate-hydroxyvalerate, polyacrylamide, polylactic acid-polyethylene glycol, polyglycolic acid-polyethyl Glycol and the like. Their molecular weight is Between 2,000 and 1,000,000 Daltons.
  • the content of the biodegradable medicinal polymeric excipient in the microsphere preparation of the present invention is from 50 to 99.8% by weight, preferably not more than 97% by weight. /. .
  • the pharmaceutically acceptable polymeric adjuvant is selected from the group consisting of polylactide-glycolide, polylactic acid, polycaprolactone, polyhydroxybutyrate-hydroxyvalerate, and the like. Preferably their molecular weight is between 3,000 and 100,000 Daltons.
  • More preferred biodegradable medicinal polymeric excipients are polylactide-glycolide, polyanhydride.
  • the most preferred biodegradable pharmaceutical polymeric excipient is polylactide-glycolide.
  • polylactide-glycolide the polymerization ratio of lactide and glycolide is
  • the terminal group of the polymer especially the terminal carboxyl group, has a great influence on the embedding rate of the amino group-containing 3,3-diphenylpropylamine derivative, the high molecular weight polylactic acid and the lactide-glycolide copolymer thereof.
  • the terminal carboxyl group content is decreased, which will result in a decrease in the embedding rate of the drug. If a carboxyl group-containing compound such as a fatty acid is added to effectively increase the embedding rate, reduce the burst release, and prolong the release cycle, it is preferred to use the slow-drying microsphere preparation of the present invention. Contains other pharmaceutical excipients.
  • the other pharmaceutically acceptable excipients which can be used in the sustained release microsphere preparation of the present invention are carboxylic acid compounds which can increase the embedding rate or reduce the burst release and prolong the dry release period, including C 1 ( )-C 3Q .
  • a saturated or unsaturated fatty acid selected from, but not limited to, palmitic acid, oleic acid, linoleic acid, linolenic acid, etc.; may also be selected from pharmaceutically acceptable other compounds containing a carboxylic acid group, including but not limited to carboxyl group-containing poly Ethylene glycol, propylene glycol, and copolymers, polypeptides, proteins, and the like thereof.
  • the other pharmaceutical excipients are contained in the microsphere preparation of the present invention in an amount of from 0 to 20% by weight, preferably from 0 to 10% by weight, more preferably from 1 to 6% by weight.
  • the particle size of the sustained release microsphere of the 3,3-diphenylpropylamine derivative of the present invention should be between 1 and 250 ⁇ m, so as to maintain a certain aging and good biodegradability. And does not affect blood circulation after injection into the body. If the particle size is too small, it is difficult to maintain long-term efficacy, and at the same time, it may block capillaries and affect microcirculation; if the particle size is too large, the initial release is too slow to reach the therapeutic effective blood concentration.
  • the sustained-release microsphere preparation of the present invention has no particular limitation on the content of the 3,3-diphenylpropylamine derivative therein as long as it can achieve the purpose of sustained release, but from ensuring a sufficiently high blood concentration and ensuring ⁇
  • the content of the derivative is less than 0.2% by weight, and a sufficiently high blood concentration cannot be ensured; otherwise, if it is higher than 50% by weight. /. , there may be no guarantee that the drug will be released smoothly, which will cause side effects.
  • the sustained release microsphere preparation of the present invention can be obtained by a conventional preparation method using a microsphere preparation, such as a solvent evaporation method, a spray drying method, and a spray extraction method.
  • the solvent evaporation method is to dissolve a 3,3-diphenylpropylamine derivative and a biodegradable medicinal polymer adjuvant and other medicinal adjuvants with an organic solvent, and inject the organic solvent phase into the pharmaceutically acceptable water.
  • the sustained release microspheres are obtained by solvent evaporation.
  • the spray drying method is to dissolve a 3,3-diphenylpropylamine derivative, a biodegradable medicinal polymer adjuvant and other medicinal excipients with an organic solvent, and to obtain a microsphere by spray drying.
  • the spray extraction method is to dissolve a 3,3-diphenylpropylamine derivative, a biodegradable medicinal polymer auxiliary material and other medicinal excipients in an organic solvent, and spray it into an organic non-solvent by extraction. Made microspheres.
  • the microspheres of the present invention are prepared by a solvent evaporation method
  • the 3,3-diphenylpropylamine derivative and the biodegradable polymeric pharmaceutical excipient and other medicinal adjuvants are first dissolved in an organic solvent to prepare an organic phase.
  • a continuous aqueous phase is prepared from a pharmaceutically acceptable water-soluble polymer compound, and the organic phase is injected into a continuous aqueous phase through a thin tube, and fully emulsified to form microspheres under vigorous stirring such as mechanical stirring or ultrasonic action.
  • the organic solvent is then volatilized to a thousand, and the formed microspheres are separated by filtration and dried. If necessary, the microspheres may be subjected to water washing, grading, etc., in a conventional manner, followed by drying under reduced pressure or lyophilization, followed by dispensing.
  • the organic solvent used should be an organic solvent having sufficient volatility, low residual and low boiling point, such as dichloromethane, chloroform, ethyl acetate, diethyl ether and a mixed solvent thereof.
  • Pharmaceutically acceptable water-soluble polymers for formulating a continuous aqueous phase include, but are not limited to, polyvinyl alcohol, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, sodium polymethacrylate, sodium polyacrylate, and the like.
  • the content of the 3,3-diphenylpropylamine derivative and the biodegradable polymer pharmaceutical excipient in the organic solvent is not limited as long as they can be dissolved in the organic solvent, but from the feasible concentration and
  • the concentration of the biodegradable polymer excipient is preferably from 1 to 30% (w/v) from the viewpoint of the balance of the viscosity and the use of the organic solvent as little as possible.
  • a continuous aqueous phase is prepared using polyvinyl alcohol, sodium carboxymethylcellulose, polyvinylpyrrolidone, sodium polymethacrylate, or sodium polyacrylate
  • concentration thereof is also not particularly limited, but based on their solubility in water, preferred
  • the content is 0. 01-12. 0% (w/v), more preferably 0. 01-10. 0% (w/v), most preferably 0.1-5% (w/v).
  • the volume ratio of the organic phase to the aqueous phase should be sufficient to sufficiently disperse the organic phase in the aqueous phase to form microspheres of sufficiently fine particle size and uniformity, but If the water phase is too much, the post-treatment is complicated and the cost is increased.
  • the volume ratio of the organic phase to the aqueous phase is approximately 1: 4-1: 1 00.
  • a sustained release microsphere preparation of a 3,3-diphenylpropylamine derivative is prepared by spray drying
  • a 3,3-diphenylpropylamine derivative, a biodegradable medicinal polymer auxiliary material, and an organic solvent can be used.
  • the other medicinal excipients are fully dissolved and formulated into an organic solution, filtered, and microspheres are prepared by conventional spray drying. If necessary, the microspheres may also be subjected to water washing, grading, etc., and then dispensed according to a conventional method.
  • the organic solvent that can be used includes However, it is not limited to dichloromethane, chloroform, ethyl acetate, dioxane, diethyl ether, acetone, tetrahydrofuran, acetic acid, a mixed solvent composed of them, and the like.
  • the organic solvent is capable of dissolving the pharmaceutical excipient
  • the biodegradation is preferably high.
  • the concentration of molecular pharmaceutical excipients is 1-30% (w/v).
  • the 3,3-diphenylpropylamine derivative microspheres are prepared by spray extraction, the 3,3-diphenylpropylamine derivative, the biodegradable medicinal polymer adjuvant and other pharmaceutical excipients can be fully dissolved by an organic solvent.
  • Formulated into an organic solution sprayed to an organic non-solvent or water at normal temperature or high temperature or low temperature, and extracted to form microspheres. If necessary, the microspheres may be washed, classified, etc. according to conventional methods. Processing, then sub-packaging.
  • organic solvents which may be used include, but are not limited to, dichloromethane, chloroform, ethyl acetate, dioxane, diethyl ether, acetone, tetrahydrofuran, glacial acetic acid, and a mixed solvent composed of them.
  • organic nonsolvents which can be used include, but are not limited to, decyl alcohol, ethanol, propanol, isopropanol, petroleum ether, alkanes, paraffin oil, and the like, and mixed non-solvents composed of them.
  • the organic solvent is capable of dissolving the pharmaceutical excipient
  • the biodegradation is preferably high.
  • the concentration of molecular pharmaceutical excipients is 1-30% (w/v).
  • the solvent evaporation method is preferably a spray drying method in comparison with the spray drying method, and the solvent evaporation method is preferred from the viewpoints of ease of handling and the like, and from the viewpoint of controlling the particle size of the microspheres and reducing the initial release.
  • the microspheres of the 3,3-diphenylpropylamine derivative of the present invention may be subjected to particle size fractionation or may be classified and removed if the particle diameter is sufficient. After washing and drying, it is dispensed according to the prescribed dosage to prepare a powdery injection, which is prepared into a suspension injection in situ.
  • the powder injection can be directly prepared from the above microspheres, and is uniformly suspended by using a diluted solution containing physiological saline for injection and a suspending agent before use to prepare a suspension injection.
  • a predetermined amount of isotonic salts, mannitol, glucose, and a suspending agent may be mixed and dried in a microsphere preparation, and then lyophilized, and a predetermined amount of pure water for injection may be added thereto before use to prepare an injection solution.
  • the use of the present invention for treating or adjunctively treating diseases associated with muscarinic receptors and unstable or overactive bladder such as urgency or stress urinary incontinence, impulsive incontinence, urgency or urinary frequency is
  • the administration of the 3,3-diphenylpropylamine derivative of the present invention to a patient in need of the above treatment is carried out.
  • Modes of administration include, but are not limited to, intramuscular injection, subcutaneous injection, intradermal injection, intra-abdominal injection, and the like. From the viewpoint of convenience of administration, administration by intramuscular administration and subcutaneous injection is preferred.
  • the sustained release microsphere preparation of the 3,3-diphenylpropylamine derivative of the present invention is administered at a dose of (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxyl
  • a dose of (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxyl) for a patient weighing 60 kg, is administered in an amount of 10-120 mg per injection, once a week or weeks.
  • Appropriate changes can be made according to the actual conditions of the patient's age, weight, disease state, etc., which are within the judgment of those skilled in the art.
  • the sustained release microsphere preparation of the 3,3-diphenylpropylamine derivative of the present invention can achieve sustained release of the 3,3-diphenylpropylamine derivative.
  • the mechanism of action of the sustained-release microspheres of the present invention is that when it is injected into the body, it gradually diffuses with the blood circulation, and during the circulation of the body, the biodegradable polymer resin such as polylactide- Although glycolide is insoluble in water, it can be gradually degraded by the body. As it gradually degrades, the drugs contained in the microspheres are gradually released, thereby achieving sustained release and long-acting effects.
  • the sustained release microsphere preparation using the 3,3-diphenylpropylamine derivative of the present invention can realize the long-acting effect of the 3,3-diphenylpropylamine derivative which is not realized in the prior art, for example, not less than The interval of one week, preferably not less than 15 days, can even be administered at intervals of up to 1 month, so it is expected to improve unstable or overactive bladder such as The quality of life of patients with urgency or stress urinary incontinence, impulsive incontinence, urgency or frequent urination, while reducing the amount of human and material resources required for daily dosing.
  • Figure 1 is a line graph showing the daily or cumulative release rate of the sustained release microsphere preparation prepared according to the method of Example 1 in the simulated front discharge of PH 7.4.
  • Figure 2 is a line graph of daily or cumulative dry release rate of the sustained release microsphere preparation prepared according to the method of Example 3 in a simulated release solution of pH 7.4.
  • Figure 3 is a line graph of the daily or cumulative release rate of the sustained release microsphere preparation prepared according to the method of Example 4 in a simulated release solution of pH 7.4.
  • Figure 4 is a line graph of the daily or cumulative release rate of the sustained release microsphere preparation prepared according to the method of Example 9 in a simulated release solution of pH 7.4.
  • Figure 5 is a line graph of the daily or cumulative release rate of the sustained release microsphere preparation prepared according to the method of Example 11 in a simulated release solution of pH 7.4.
  • Figure 6 is a line graph of the daily or cumulative release rate of the sustained release microsphere preparation prepared according to the method of Example 13 in a simulated dry discharge solution of pH 7.4. detailed description
  • the particle size of the microspheres in the examples was measured by a L2000 type fully automatic laser particle size analyzer (Beckman Coulter) which is familiar to those skilled in the art.
  • the plasma concentration is determined by high performance liquid chromatography (HPLC) and can be determined according to literature methods, for example, Journal of Modern Applied Pharmacy, 1993, 10 (1), 51-52; Chinese Journal of Pharmaceutical Industry, 1999, 30 (8), 363-365 and so on.
  • HPLC high performance liquid chromatography
  • the embedding rate of compound la is only 34%.
  • the obtained sustained-release microspheres were tested in vivo against the dogs.
  • the microspheres were suspended in physiological saline for injection, and the intramuscular injection was administered once at a dose of 2.4 mg/kg.
  • Blood was taken from the first to the 15th day after administration and HPLC-MS was performed.
  • the plasma concentration was 0.2. Up to 5 ng/ml. It is proved that the slow-drying microsphere can achieve a smooth release at least 15 days.
  • the embedding rate of compound la is only twenty one%.
  • the obtained sustained-release microspheres were tested in vivo against the dogs.
  • the microspheres were suspended in physiological saline for injection, and the intramuscular injection was administered once at a dose of 3.2 mg/kg.
  • Blood was taken and analyzed by HPLC-MS within 1 to 20 days after administration. The blood concentration was 0.2. Up to 5 ng/ml. It is proved that the slow-drying microsphere can achieve smooth dry release at least 20 days.
  • the obtained sustained-release microspheres were tested in vivo for comparison with the dog.
  • the microspheres were suspended in physiological saline for injection, and the intramuscular injection was administered once at a dose of 3.7 mg/kg.
  • blood was taken and detected by HPLC-MS, and the blood concentration was 0.2 to 3 ng/ml 0 proved that the sustained release microspheres can achieve a smooth release for at least 30 days.
  • Example 10 Weigh out 1. Og (R) -N, N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine (Compound II), 9.
  • a buffer solution sodium phosphate buffer solution
  • a certain pH value ⁇ 7.4
  • the release test was carried out by simulating in vivo conditions.
  • Sampling method Centrifuge the tube at 3600 rpm for 20 min, accurately absorb 3 ml of the solution, and add 3 ml of release medium to the tube, and take out the liquid for HPLC.
  • Sampling time (days): 0, 1, 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29 or 0, 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30.
  • the 0th day refers to the concentration of the drug before administration on the day of administration.
  • the cumulative release on day 2 was 10.9.
  • the release on the third day of the day ( 15.2-10.9) ⁇ ( 3-2) 4.3 analogy.
  • Example 17 The in vitro release effects of the microsphere formulations of Examples 1, 3, and 4 at pH 7.4 are shown in Figures 1-3, respectively.
  • Example 17
  • Example 13 Accumulation 0 2.3 3.5 10.5 15.2 22.0 30.4 41.8 52.6 Implementation . Same day 0 32.0 17.6 10.6 4.4 3.4 3.0 1.6 0.9
  • the sustained release microsphere preparation of the 3,3-diphenylpropylamine derivative of the present invention can stably release the drug for up to 14 days or longer. Therefore, for patients with diseases related to muscarinic receptors and patients with unstable or overactive bladder such as urgency or stress urinary incontinence, impulsive incontinence, urgency or urinary frequency, it can be greatly reduced.
  • the number of drugs, while effectively controlling the dose, avoids the appearance of side effects.
  • the invention adopts a biodegradable polymer to embed a 3,3-diphenylpropylamine derivative to prepare an injection microsphere preparation, and the injection can be maintained for 14 days or longer, for Suspected to be a gospel for patients with muscarinic receptor-related diseases and unstable or overactive bladder such as tight or stress urinary incontinence, impulsive incontinence, urgency or frequent urination.

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Abstract

L'invention concerne une préparation microsphérique à libération prolongée injectable de 3,3-diphénylpropylamine, son procédé de préparation et son application. Ladite préparation microsphérique à libération prolongée est constituée de 3,3-diphénylpropylamine de formule (I) suivante, de ses énantiomères ou racémiques optiques et d'un ou plusieurs adjuvants de poids moléculaire élevé biodégradables médicinaux et autres adjuvants médicinaux, R1, R2, R3, R4 et R5 étant tels que définis dans les revendications. La préparation microspéhrique à libération prolongée injectable selon l'invention est utilisée pour le traitement ou le traitement complémentaire de maladies liées au récepteur muscarinique et à une vessie instable ou hyperactive telles que l'incontinence urinaire par impériosité ou à l'effort, l'incontinence par impériosité, l'urgence urinaire ou la fréquence urinaire, etc.
PCT/CN2005/002277 2004-12-23 2005-12-22 Préparation microsphérique à libération prolongée injectable de dérivés de 3,3-diphénylpropylamine servant d'antagonistes du récepteur muscarinique WO2006066509A1 (fr)

Applications Claiming Priority (2)

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CN2004101017218A CN1795845B (zh) 2004-12-23 2004-12-23 作为毒蕈碱受体拮抗剂的3，3-二苯基丙胺衍生物注射用缓释微球制剂
CN200410101721.8 2004-12-23

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010010464A2 (fr) * 2008-07-21 2010-01-28 Actavis Group Ptc Ehf Fésotérodine essentiellement exempte d’impureté dihydroxy
WO2010018484A1 (fr) * 2008-08-14 2010-02-18 Pfizer Limited Nouvelles utilisations de dérivés de diisopropylamine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1356894A (zh) * 1999-05-18 2002-07-03 施瓦茨制药有限公司 含有托特罗定的经皮治疗系统(tts)
CN1393220A (zh) * 2001-07-03 2003-01-29 山东绿叶制药股份有限公司 石杉碱甲及其衍生物或其盐的注射用缓释微球及其制备方法
CN1526372A (zh) * 2003-05-15 2004-09-08 上海复康医药科技发展有限公司 一种抑制突释效应的长效注射剂

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100353935C (zh) * 1999-11-11 2007-12-12 法马西雅公司 含托特罗定的药物制剂及其应用
CN1164265C (zh) * 2002-01-09 2004-09-01 南京美瑞制药有限公司 酒石酸托特罗定的缓控释制剂及其制备方法
CN1437933A (zh) * 2003-03-28 2003-08-27 中国科学院长春应用化学研究所 可生物降解性高分子材料包裹利福平微球的制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1356894A (zh) * 1999-05-18 2002-07-03 施瓦茨制药有限公司 含有托特罗定的经皮治疗系统(tts)
CN1393220A (zh) * 2001-07-03 2003-01-29 山东绿叶制药股份有限公司 石杉碱甲及其衍生物或其盐的注射用缓释微球及其制备方法
CN1526372A (zh) * 2003-05-15 2004-09-08 上海复康医药科技发展有限公司 一种抑制突释效应的长效注射剂

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010010464A2 (fr) * 2008-07-21 2010-01-28 Actavis Group Ptc Ehf Fésotérodine essentiellement exempte d’impureté dihydroxy
WO2010010464A3 (fr) * 2008-07-21 2010-12-23 Actavis Group Ptc Ehf Fésotérodine essentiellement exempte d’impureté dihydroxy
WO2010018484A1 (fr) * 2008-08-14 2010-02-18 Pfizer Limited Nouvelles utilisations de dérivés de diisopropylamine

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