WO2006066509A1

WO2006066509A1 - Injectable sustained release microspheric preparation of 3,3-diphenylpropylamine derivatives as muscarinic receptor antagonists

Info

Publication number: WO2006066509A1
Application number: PCT/CN2005/002277
Authority: WO
Inventors: Youxin Li
Original assignee: Youxin Li
Priority date: 2004-12-23
Filing date: 2005-12-22
Publication date: 2006-06-29
Also published as: CN1795845A; CN1795845B

Abstract

The invention relates to injectable sustained release microspheric preparation of 3,3-diphenylpropylamine, it’s preparing process and application. The said sustained release microspheric preparation consists of 3,3-diphenylpropylamine of formula (I) as follows, its optical enantiomers or racemates and one or more medicinal biodegradable high-molecular auxiliary material and other medicinal auxiliary material, wherein the definition of R1, R2 R3 R4 and R5 sees the claims. The injectable sustained release microspheric preparation according to the invention is used for treatment or supplementary treatment of diseases related to the muscarinic receptor and unstable or overactive bladder such as urgency or stress urinary incontinence, urge incontinence, urinary urgency or frequency, etc.

Description

3, 3-diphenyl as a muscarinic receptor antagonist

'Lendamine microsphere preparation for injection of propylamine derivative

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.

(la) (II)

It has been reported that (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxydecylphenyl)-3-phenylpropylamine ( la) and (R)-N, N-di Isopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine (tolterodine) (Π) is a muscarinic receptor antagonist (EP0325571; W094/11337), which It can be used to treat unstable or overactive bladders such as urgency or stress urinary incontinence, impulsive incontinence, urgency or urinary frequency, for example, Famasia's tolterodine tartrate oral tablets or gelatin (EP0325571) ) has entered the market. Some of their derivatives or prodrugs have been found to have similar effects by modifying their structure (EP0325571, EP1077912).

Clinical studies have shown that 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. -carboxyl and N-desalkyl-5-carboxylate a base metabolite, wherein (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxydecylphenyl)-3-phenylpropylamine has pharmacological activity. Although tolterodine its metabolite (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine is a muscarinic receptor antagonist Agent, but for most patients, its main pharmacological action is its metabolite (R)-N, N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-benzene Propylamine

(Eur. J. Pharmacol. 327 (1997), 195-207; EP1077912) ₀ experiments show that (R) - Ν, N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl) The muscarinic receptor antagonism of -3-phenylpropylamine is ten times higher than that of tolterodine itself.

(W094/11337). Clinical studies have also shown that only part of tolterodine is converted to (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxydecylphenyl)-3- Phenylpropylamine, especially in patients with impaired liver function, tolterodine is converted to (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3 The ability of phenylpropylamine is greatly reduced, while other inactive metabolites are increased, resulting in reduced efficacy and increased side effects.

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.

Oral 3, 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. Though However, 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. A new injectable long-acting sustained release dosage form of 3,3-diphenylpropylamine. Summary of the invention

It is an object of the present invention to provide a long-acting preparation for injection of a 3,3-diphenylpropylamine derivative, which is capable of reducing the frequency of use of a drug from one or more times a day to one week, two weeks, one month or even Once every 2 months, the number of medications is greatly reduced, and the bioavailability and therapeutic effect of the drugs are improved, thereby alleviating the suffering of the patients and improving their quality of life.

Accordingly, 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.

Specifically, the 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:

I)

among them,

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.

The term "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. According to a preferred embodiment of the present invention, 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.

Table 1

Compound Rl R2 R3 R4 R5 configuration la hydrogen atom 5-hydroxydecyl isopropyl isopropyl hydrogen atom R II hydrogen atom 5-mercaptoisopropyl isopropyl hydrogen atom R

III acetyl 5-hydroxydecyl isopropyl propyl hydrogen atom R

IV isobutyryl 5-hydroxydecyl isopropyl propyl hydrogen atom R

V acetyl 5-mercaptoisopropyl isopropyl hydrogen atom R

VI isobutyryl 5-indenylisopropylisopropyl hydrogen atom R The above compound ( la) -(VI) is named (R) -N, N-diisopropyl-3-(2-hydroxy-) 5-(hydroxymethylphenyl)-3-phenylpropylamine; (R)-N,N-diisopropyl-3-(2-hydroxy-5-mercaptophenyl)-3-phenylpropylamine (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine monoacetate; (R)-N, N-diisopropyl-3-(2-hydroxy-5-hydroxydecylphenyl)-3-phenylpropylamine monoisobutyrate; (R)-N,N-diisopropyl-3- ( 2-hydroxy-5-methylphenyl)-3-phenylpropylamine acetate; and (R)-N,N-diisopropyl-3-(2-hydroxy-5-nonylphenyl)- 3-Phenylpropylamine isobutyrate.

Among the above compounds, (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine (Compound Ia), (R)- N,N-diisopropyl-3-(2-hydroxy-5-nonylphenyl)-3-phenylpropylamine (Compound 11), and (R)-N,N-diisopropyl-3- (2-Hydroxy-5-hydroxydecylphenyl)-3-phenylpropylamine monoisobutyrate (Compound IV).

According to the present invention, 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.

According to the present invention, 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. /. .

Preferably, 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. For polylactide-glycolide, the polymerization ratio of lactide and glycolide is

95: 5-5: 95, preferably 25: 75-75: 25, most preferably about 50:

50.

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.

According to the present invention, 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 μm, 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.

According to the present invention, 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重量重量的优选的优选的优选的优选的优选为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为为。 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.

Specifically, 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. In the emulsion prepared by the polymer, 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.

When 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. In addition, 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.

In the above operation, from the operational point of view, 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.

In the preparation of the organic phase, 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.

When a continuous aqueous phase is prepared using polyvinyl alcohol, sodium carboxymethylcellulose, polyvinylpyrrolidone, sodium polymethacrylate, or sodium polyacrylate, the 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).

When the organic phase is injected into the aqueous phase and stirred vigorously to form microspheres, 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. In combination with the above two aspects, the volume ratio of the organic phase to the aqueous phase is approximately 1: 4-1: 1 00.

When 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.

When the microspheres are prepared by the above spray drying 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.

In the preparation of the organic phase, as long as the organic solvent is capable of dissolving the pharmaceutical excipient, there is no limitation on the content of the organic solvent in the organic solvent, but from the viewpoint of the balance of the feasible concentration and the less use of the organic solvent, the biodegradation is preferably high. The concentration of molecular pharmaceutical excipients is 1-30% (w/v).

When 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.

When the microspheres are prepared by the above spray extraction method, 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.

When the microspheres are prepared by the above spray extraction method, 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 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.

According to the present invention, 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 For example, nonylphenyl)-3-phenylpropylamine, 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. Although not limited to the prior art, it can be considered that 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. DRAWINGS

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

Hereinafter, the preparation method and sustained release effect of the 3,3-diphenylpropylamine derivative microsphere preparation of the present invention will be further described by way of examples, but the invention is not limited at all.

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. Example 1

0.8 g of (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine (Compound la), 9.2 g of polylactide-B Ester (lactide: glycolide = 50: 50, molecular weight 25,000), palmitic acid 300 mg dissolved in 50 ml of dichloromethane, and dripped into 2500 ml of 0.5% PVA aqueous solution under vigorous stirring (1200-1600 rpm) After the completion of the dropwise addition, vigorous stirring was continued for 3 to 10 minutes, then the stirring speed was lowered to 300 rpm, the solvent was evaporated for 4 to 6 hours, filtered, and the microspheres were washed three times with distilled water and lyophilized. The particle size is 1-200 μηη, the drug content is 5.4% by weight, and the embedding rate is 69.5%.

Under the same conditions, if palmitic acid is not added, 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. Example 2

Weigh 0.5g of (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine (Compound la), 9.5g of polylactide-B Lactide (lactide: glycolide = 50: 50, molecular weight 13,000), prepared according to the method of Example 1 to obtain a drug content of 4.7% by weight, a particle size of 1-200 μπι microspheres, the embedding rate It is 94%. Example 3

Weigh 0.8 g of (R)-Ν, Ν-diisopropyl-3-(2-hydroxy-5-hydroxydecylphenyl)-3-phenylpropylamine (Compound la), 9.4 g of polylactide-B Lactide (lactide: glycolide = 50: 50, molecular weight 35,000), 400 mg palmitic acid, prepared according to the method of Example 1 to obtain a drug content of 3.8% by weight, a particle size of 1-200 μηη microspheres The embedding rate is 51%.

Under the same conditions, if palmitic acid is not added, 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. Example 4

Weigh out 1. Og (R) -N, N-diisopropyl-3-(2-hydroxy-5-hydroxydecylphenyl)-3-phenylpropylamine (Compound la), 9. Og polylactide - glycolide (lactide: glycolide = 75: 25, molecular weight of 11,000), prepared according to the method of Example 1 to obtain microspheres having a drug content of 7% by weight and a particle diameter of 1-200 μm. Its embedding rate is 70%. Example 5

Weigh out 1. Og (R) -N, N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine (Compound la), 9. Og polylactide - glycolide (lactide: lactide = 50: 50, molecular weight 25000), 400 mg palmitic acid, 200 ml of dichloromethane, stirred until fully dissolved, prepared by conventional spray drying method Amounts of microspheres with a particle size of 1-100 μm, sterilized, and dispensed. Example 6

Weigh 1.0 g of (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxydecylphenyl)-3-phenylpropylamine (Compound la), 9.0 g of polylactide-B Lactide (lactide: glycolide = 50: 50, molecular weight 25000), 300 mg palmitic acid, 100 ml of dichloromethane, stirred until fully dissolved, sprayed into 2000 ml of petroleum ether by conventional spraying, extracted and filtered The microspheres having a drug content of 10% by weight and a particle diameter of 1-ΙΟΟμπι were prepared by drying, sterilized, and dispensed. Example 7

Weigh 1·Og(R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxydecylphenyl)-3-phenylpropylamine monoisobutyrate (Compound IV), 9 Og polylactide-glycolide (lactide: glycolide = 50: 50, molecular weight 13,000), prepared according to the method of Example 1 with a drug content of 9.5 wt% and a particle size of 1-200 μιη Microspheres, embedding rate is 95%. Example 8

Weighing 1. Og (R) -N, N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine monoisobutyrate (Compound IV), 9 Og polylactide-glycolide (lactide: glycolide = 50: 50, molecular weight 25,000), prepared according to the method of Example 1 to obtain a drug content of 7.1 wt%. The microspheres with a particle size of 1-200 μm have an embedding rate of 71%. Example 9

1. Og (R) -N, N-diisopropyl-3-(2-hydroxy-5-nonylphenyl)-3-phenylpropylamine (Compound 11), 9.0 g of polylactide-B The ester (lactide: glycolide = 50: 50, molecular weight 5.00) was dissolved in 50 ml of dichlorosilane, and it was dripped into 2500 ml of 0.5% PVA aqueous solution under vigorous stirring (1200-1600 rpm). After continued vigorous stirring for 3-10 minutes, then the stirring speed was reduced to 300 rpm, the solvent was evaporated for 4-6 hours, filtered, and the microspheres were washed three times with distilled water, and lyophilized to obtain a drug content of 6.8 wt% and a particle diameter of 1-200 μm. Microspheres, embedding rate was 68%.

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. Within 1 to 30 days after administration, 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. Og polylactide - Glycolide (lactide: glycolide = 50: 50, molecular weight 13,000), microspheres having a drug content of 7.4% by weight and a particle size of 1-200 μm were prepared according to the method of Example 1, and the embedding rate was 74. %. Example 11

Weigh out 1. Og (R) -N, N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine (Compound II), 9. Og polylactide- Glycolide (lactide: glycolide = 50: 50, molecular weight 35,000), prepared according to the method of Example 1 to obtain a drug content of 6.7% by weight, a particle size of 1-200 μηη microspheres, embedding rate It is 67%. Example 12

Weigh 1.5 g of (R) N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine (Compound 11) ', 4.25 g of polylactide-glycolide ( Lactide: glycolide = 50: 50, molecular weight 35,000), 4.25 g polylactide-glycolide (lactide: glycolide-50: 50, molecular weight 13,000), according to Example 1 The method prepared a microsphere having a drug content of 10.8% by weight and a particle diameter of 1-200 μm, and the embedding rate was 72%. Example 13

Weigh 1.0 g of (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine (Compound II), 9.0 g of polylactide-B-cross The ester (lactide: glycolide = 75: 25, molecular weight: 11,000) was prepared according to the method of Example 1 to give a drug content of 9.0 by weight. /. The microspheres with a particle size of 1-200 μm have an embedding rate of 90%. Example 14

Weigh 1.0 g of (R)-N,N-diisopropyl-3-(2-hydroxy-5-mercaptophenyl)-3-phenylpropylamine (Compound II), 9.0 g of polylactide-B-cross Ester (lactide: C Lactide = 50: 50, molecular weight is 2, 000), adding 200 ml of dichloromethane, stirring until fully dissolved, using a conventional spray drying method to prepare microspheres having a drug content of 10% by weight, and having a particle size of 1-100 μm, Sterilize, dispense. Example 15

Weigh out 1. Og (R) -N, N-diisopropyl-3-(2-hydroxy-5-nonylphenyl)-3-phenylpropylamine (Compound II), 9. Og polylactide- Glycolide (lactide: glycolide = 50: 50, molecular weight 25000), add 100ml of dichloromethane, stir until fully dissolved, spray into 2000ml petroleum ether by conventional spray method, extract and filter, after drying The microspheres having a drug content of 10% by weight were measured to have a particle size of 1-100 μm, sterilized, and dispensed. Example 16:

(R)-Ν, Ν-diisopropyl-3-(2-hydroxy-5-hydroxydecylphenyl)-3-phenylpropylamine microsphere or (R)-Ν, Ν-diisopropyl- In vitro release test of 3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine monoisobutyrate microsphere preparation.

It has been found that a buffer solution (sodium phosphate buffer solution) with a certain pH value (ΡΗ7.4) has a similar drug release behavior as the body. Although its environment is not exactly the same as the human body environment, it is generally considered to be able to express the body's release. mode. Using the microspheres of Examples 1-4, 7 and 8, the release test was carried out by simulating in vivo conditions.

Experimental equipment: Constant temperature oscillator, centrifuge.

Experimental conditions: Temperature: 37 ± 0.5. C, speed: 30 rpm.

Experimental method: Weigh accurately about 1 mg of the experimental sample, place it in a plastic centrifuge tube with a volume of 5 ml, add 5 ml of release medium (pH=7.4 sodium phosphate buffer solution) to a constant temperature oscillator, and maintain a certain temperature. And speed, sample on time.

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 test results are summarized in Table 2.

Table 2

Percent release (%)

Sample drug content

No. μ g/mg mode

0 1 2 3 5 7 9 11 13 Implementation Day 0 6. 5 4. 4 4. 3 8. 0 9. 7 6. 7 5. 2 5. 2

38

example 1

Cumulative 0 6. 5 10. 9 15. 2 31. 2 50. 6 64. 0 74. 4 84. 8 On the day of implementation 0 35. 9 26. 0 14. 1 6. 0 3. 0 1. 9 0. 7 0. 6

47

Example 2

Cumulative 0 35. 6 61. 9 76. 0 88. 0 94. 0 97. 8 99. 2 100 On the day of implementation 0 2. 5 2. 9 3. 4 3. 9 4. 2 5. 0 4. 1 3. 6

65

Example 3

Cumulative 0 2. 5 5. 4 8. 8 16. 6 25. 0 35. 0 43. 2 50. 4 On the day of implementation 0 1. 2 0. 9 1. 5 3. 5 4. 1 5. 6 4. 2 5. 3

70

Example 4

Cumulative 0 1. 2 2. 1 3. 6 1 0. 6 18. 8 30. 0 38. 4 49. 0 On the day of implementation 0 39. 5 24. 4 1 3. 6 5. 3 2. 8 1. 9 0 . 8 0. 5

95

Example 7 Accumulation 0 39. 5 63. 9 77. 5 88. 1 93. 7 97. 5 99. 1 100 On the day of implementation 0 1 0. 3 4. 2 5. 1 1 0. 0 7. 8 5. 8 4 . 4 3. 4

71

Example 8

Cumulative 0 10. 3 14. 5 19. 6 39. 6 55. 2 66. 8 75. 6 82. 5

Table 2 (continued)

The amount released on the day is calculated from the cumulative release of the day. Specifically, it is presumed that the drug release rate does not change in the two measurement intervals. Expressed by the formula, the amount released on the day = (accumulated release amount of the day - cumulative release amount measured the previous time) ÷ The number of days between the current measurement and the previous measurement.

For example, in Example 1, the release amount on the 0th day is 0, the cumulative release amount on the first day is 6.5, and the release amount on the first day is = (6.5-0) ÷ (1-0) = 6.5. The cumulative release on day 2 was 10.9. The release amount on the second day is 9-6.5) ÷ (2-1) = 4.4. The cumulative release on the third day 15. The release on the third day of the day ( 15.2-10.9) ÷ ( 3-2) = 4.3 analogy.

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

(R)-N,N-diisopropyl-3-(2-hydroxy-5-mercaptophenyl)-3-phenylpropane In vitro release test of amine microspheres.

Using the microspheres of Examples 9-14, the release test was carried out by simulating in vivo conditions, and the test apparatus, conditions and methods used were as described in Example 16. The results are shown in Table 3. Table 3 Percentage (%)

Drug content

#p号

Mg/mg mode

0 1 2 4 6 8 10 12 14 Implementation Day 0 2.6 4.9 5.1 3.5 3.6 3.5 3.8 3.5

68

Example 9

Accumulation 0 2.6 7.5 17.7 24.7 31.9 38.9 46.5 53.5 Implementation Day 0 23.0 14.6 8.1 6.6 5.0 4.1 3.4 2.2

74

Example 10

Accumulation 0 23.0 37.6 53.8 67.0 77.0 85.2 92.8 96.4 Implementation Day 0 1.9 0.5 0.7 0.9 2.3 3.6 3.4 3.7

74

Example 11

Accumulation 0 1.9 2.4 3.8 5.6 10.2 17.4 24.2 31.6 Implementation Day 0 7.3 13.1 6.2 4.6 4.2 4.0 4.1 3.4

108

Example 12

Accumulation 0 7.3 20.4 32.8 42.0 50.4 58.4 66.6 73.4 Implementation Day 0 2.3 1.2 3.5 4.7 3.4 4.2 5.7 5.4

90

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

100

Example 14 Accumulation 0 32.0 49.6 70.8 79.5 86.2 92.2 95.4 97.2

Table 3 (continued)

As can be seen from Table 3, 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 in vitro release effect of the microsphere preparation of Example 9, 1 1 and 1 3 under the condition of pH 7.4 is shown in Figures 4-6. Industrial applicability

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.

Claims

A sustained release microsphere preparation for injection of a 3,3-diphenylpropylamine derivative, characterized in that the sustained release microsphere preparation is a 3,3-diphenylpropylamine derivative represented by the following formula (I) , an optical enantiomer or racemate thereof, a prodrug or analog thereof or a pharmaceutically acceptable salt thereof, and one or more biodegradable pharmaceutically acceptable polymeric excipients and optionally other pharmaceuticals Excipient composition:

(I) where '

R1 represents a hydrogen atom, an alkanoyl group or -C,. Aroyl

R2 represents a hydrogen atom, C "C ₆ alkyl, hydroxyl or alkyl;

R3 and R4 each independently represent a hydrogen atom or a C-Ce alkyl group;

R5 represents a hydrogen atom, a halogen, a C "C ₆ alkyl group, an alkyl group, a C-C ₆ alkoxy group.

2. The sustained release microsphere preparation of claim 1, wherein said 3,3-diphenylpropylamine derivative is selected from the group consisting of:

(R) -N,N-diisopropyl-3-(2-hydroxy-5-hydroxydecylphenyl)-3-phenylpropylamine; (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine;

(R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine monoacetate;

(R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropylamine monoisobutyrate;

(R)-N,N-diisopropyl-3-(2-hydroxy-5-nonylphenyl)-3-phenylpropylamine acetate;

(R) -N,N-diisopropyl-3-(2-hydroxy-5-nonylphenyl)-3-phenylpropylamine isobutyrate;

Or a pharmaceutically acceptable salt thereof.

The sustained release microsphere preparation according to claim 1 or 2, wherein the pharmaceutically acceptable polymeric adjuvant is selected from the group consisting of polylactide-glycolide, polylactic acid, polyglycolic acid, poly-3-hydroxybutyrate, and poly One or more of a lactone, a polyanhydride, a polyhydroxybutyrate-hydroxyvalerate copolymer, a polypropylene dextran, a polylactic acid-polyethylene glycol, a polyglycolic acid-polyethylene glycol, The molecular weight is between 2,000 and 1,000,000 Daltons.

The slow-drying microsphere preparation according to claim 3, wherein the pharmaceutically acceptable polymeric adjuvant is selected from the group consisting of polylactide-glycolide, polylactic acid, polycaprolactone, polyhydroxybutyrate-hydroxyvalerate copolymerization. Preferred is polylactide-glycolide.

The sustained release microsphere preparation of claim 4, wherein said polylactide-glycolide has a molecular weight of between 3,000 and 100,000 Daltons.

6. The sustained release microsphere preparation of claim 4 or 5, wherein the polymerization ratio of lactide to glycolide in the polylactide-glycolide is between 95:5 and 5:95.

7. The sustained release microsphere preparation according to claim 1 or 2, which comprises other pharmaceutically acceptable adjuvants, wherein the content of the other pharmaceutically acceptable adjuvant in the microsphere preparation is 0-20% by weight, preferably 0-10% by weight, More preferably, it is 1-6% by weight.

8. The sustained release microsphere preparation of claim 1 or 2, wherein the other pharmaceutical excipient is selected from the group consisting of C _1Q - c ₃ . a saturated or unsaturated fatty acid such as palmitic acid, oleic acid, linoleic acid, linolenic acid, etc., and other pharmaceutically acceptable carboxylic acid-containing compounds such as carboxyl group-containing polyethylene glycol, propylene glycol, and copolymers thereof, Polypeptides, proteins, etc.

9. The method for preparing a sustained release microsphere preparation of a 3,3-diphenylpropylamine derivative according to claim 1, wherein the method comprises:

(a) dissolving the 3,3-diphenylpropylamine derivative as defined in claim 1 and the biodegradable polymeric pharmaceutical excipient and other pharmaceutical excipients according to any one of claims 3 to 8 with an organic solvent, The organic solvent phase is injected into a continuous aqueous phase prepared by using a pharmaceutically acceptable water-soluble polymer to form microspheres, and then the organic solvent is volatilized, and filtered to obtain a sustained release microsphere preparation;

Or

(b) dissolving the 3,3-diphenylpropylamine derivative as defined in claim 1 and the biodegradable polymeric pharmaceutical excipient according to any one of claims 3 to 8 and other pharmaceutical excipients with an organic solvent, And preparing the microsphere preparation by spray drying;

Or

(c) dissolving the 3,3-diphenylpropylamine derivative as defined in claim 1 and the biodegradable polymeric pharmaceutical excipient according to any one of claims 3 to 9 and other pharmaceutical excipients with an organic solvent, The spray method is used to spray an organic non-solvent or water, and the microsphere preparation is obtained by extraction.

10. The sustained release microsphere preparation of the 3,3-diphenylpropylamine derivative according to claim 1 for use in the preparation of a therapeutic or adjuvant treatment for a muscarinic receptor-related disease and an unstable or hyperactive bladder such as Use of drugs for urgency or stress urinary incontinence, impulsive incontinence, urgency or frequent urination.