WO2022132066A1

WO2022132066A1 - Homogenous compositions of propiverine hci formulations

Info

Publication number: WO2022132066A1
Application number: PCT/TR2020/051331
Authority: WO
Inventors: Erol KIRESEPI; Ersin Yildirim
Original assignee: Santa Farma Ilac Sanayii A.S.
Priority date: 2020-12-18
Filing date: 2020-12-18
Publication date: 2022-06-23
Also published as: EP4262799A1

Abstract

The present invention relates to a homogenous pharmaceutical composition comprising propiverine or a pharmaceutically acceptable salt thereof wherein the composition is in an oral solid dosage form with improved pharmaceutical properties.

Description

HOMOGENOUS COMPOSITIONS OF PROPIVERINE HCI FORMULATIONS

Field of the Invention

Background of the Invention

Propiverine is a typical anticholinergic agent, and also acts as a calcium channel antagonist, thus it is widely used in many countries to treat urinary incontinence, as well as frequency associated with detrusor over activity, such as neurogenic bladder and bladder irritation.

Overactive bladder is characterized by symptoms of urgency, with or without urgency incontinence, usually with frequency and notarial. Overactive bladder symptoms are suggestive of urodynamic demonstrable detrusor over activity. There are two main options for primary treatment of overactive bladder such as; bladder training and drug therapy using anticholinergic agents. Anticholinergic agents are often used to reduce detrusor over activity and improve overactive bladder symptoms.

The chemical name of propiverine is l-methyl-4-piperidyl diphenylpropoxyacetate and the empirical formula is C23H30CINO3. The compound has a molecular weight of 403.95 g/mol. The structural formula of propiverine is shown in the Formula I.

An official monograph for propiverine hydrochloride is available in Japanese Pharmacopoeia XVI (2011).

Propiverine as hydrochloride salt is an orally an anti-muscarinic agent, and which is currently on the market under the name of the MICTONORM® as immediate release and modified release for the treatment of urinary incontinence and/or increased urinary frequency and urgency in patients with overactive bladder syndrome with the authorization holder of Apogepha Arzneimittel GmbH. The immediate release tablet dosage form is marketed in the strength of 15 mg propiverine hydrochloride which is equivalent to 13.64 mg propiverine per tablet, whereas the modified release capsule dosage form is marketed in the strengths of 30 mg and 45 mg propiverine hydrochloride which are respectively equivalent to 27.28 mg and 40.92 mg propiverine per capsule.

The patent with number of DD 106643 is the basic patent first mentioned about propiverine and its salts.

EP1435915 (Apogepha Arzneimittel GmbH) relates to a prolonged-release pharmaceutical composition comprising 4 mg to 60mg of propiverine or acceptable salts thereof, where the composition is adapted for once-a-day oral administration and has specific in vitro release characteristics measured in 750 ml of 0. IN hydrochloric acid during the first hour and following measured in 750 ml pH 5.8 USP buffer using a Ph. Eur. basket method at 100 rpm and 37°C±0.5°C.

W02006046560 (Taiho Pharmaceutical) relates to an oral preparation that ensures good sensation upon administration thereof obtaining a suspension resulting from mixing of propiverine hydrochloride, a surfactant, a pH adjusting agent and water and having its pH value adjusted between 6.5 and 8.0, and subsequently granulating the suspension together with common additives for preparation.

EP2276472 (Eurand) relates to a pharmaceutical composition by comprising a plurality of controlled-release particles, wherein a core comprising a weekly basic drug, an alkaline buffer layer disposed over the core and a water insoluble polymer of the controlled release coating disposed over the alkaline buffer layer. Enteric effect is provided by multiple coatings.

CN102579404A (Guangzhou Coredes) discloses a sustained-release capsule containing propiverine hydrochloride. The sustained capsule comprises micro-pills which have uniform particle size and micro-pills comprise pill cores containing drug accounting for 75 to 97 percent and the sustained release layers accounting for 3 to 25 percent by weight percentage.

WO2012154892 (Theravida) relates to a pharmaceutical composition comprising a therapeutically effective amount of extended release propiverine, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of pilocarpine, or a pharmaceutically acceptable salt thereof. WO 2007/105229 (Panacea Biotec Ltd) relates to a novel controlled release pharmaceutical composition comprising at least one active agent(s), at least one pH dependent polymer(s), at least one pH independent polymer(s) and at least one channel forming agent(s), optionally with other pharmaceutically acceptable excipients, wherein the ratio of the pH dependent polymer and the pH independent polymer is 1 : 10 to 10:1.

EP0173928 (AB Leo) is related to a controlled-release pharmaceutical preparation having biphasic release profile, comprising a drug tablet and a coating applied on it, wherein the coating consists of a film-forming polymer which is insoluble in water and gastro-intestinal fluids and a water-soluble pore-creating material being randomly distributed in said polymer characterized in that the pore-creating material includes a drug active substance in a therapeutically effective amount.

US5695781 and US6083532 (Hallmark Pharmaceuticals, Inc., Duramed Pharmaceuticals, Inc.) related to a three-component release rate controlling matrix composition that is composed of a pH dependent polymer and an independent gelling polymer and an enteric polymer.

EP2851073 (Taiho Pharmaceutical CO LTD) relates to a superior prophylactic agent and/or therapeutic agent comprising an effective amount of 4-piperidyl diphenylpropoxy acetate (propiverine) or a salt thereof, and a pharmaceutical carrier for treating stress urinary incontinence.

EP3331502A (Santa Farma ila<? San. A.§) relates to a controlled release pharmaceutical compositions for oral administration comprising propiverine or a pharmaceutically acceptable salt thereof having biphasic in vitro release characteristics wherein said composition also comprises at least one hydrophilic polymer, at least one water soluble pore forming agent and at least two pH dependent polymers in a matrix formation. This composition provides a dissolution profile of propiverine less than 50% after nine hours and more than 85% after 24 hours as measured by USP Type I apparatus (basket) at 100 rpm, in 750 mL of 0.1N hydrochloric acid for the first hour, subsequently in 750 mL USP buffer at pH 5.8 till to nine hours, and subsequently in 750 mL of pH 6.8 USP buffer till to 24 hours.

As pharmacokinetic point of view, the resorption rate is related with the half-life duration of the substance in the organism deciding whether at the end of the dosage intervals. Thus, for acquiring a sufficient resorption rate and a sufficient extent of the resorption of the active agent over the whole region of the gastrointestinal tract with its different pH values are necessary. Propiverine is nearly completely absorbed from the gastrointestinal tract and it undergoes extensive first pass metabolism due to its weak acid.

Immediate release dosage form comprising propiverine after oral administration is absorbed from the gastrointestinal tract with maximal plasma concentrations reached after 2.3 hours and the mean absolute bioavailability is 40.5%.

For a therapeutically effective blood level of propiverine, the exact observance of the intake intervals is necessary, which leads to problems especially in elderly patients and the main group with hypertonic functional states of the bladder. Therefore, it is desirable to reduce the multiple administration per day with all its known effects to a single dose with the same or improved therapeutic effect.

Therefore, the controlled release dosage form of propiverine is developed with absorbing from the gastrointestinal tract with maximal plasma concentrations reached after 9 to 10 hours and the mean absolute bioavailability is 60.8 ± 17.3%.

Based on the prior arts are shown in the above, many studies have been conducted to provide sustained release compositions with various release control agents.

In the present invention, a homogenous pharmaceutical composition comprising propiverine and at least one pharmaceutically acceptable excipient is developed in oral solid dosage form with proper release profile characteristics.

Summary of the Invention

The object of this invention is to develop a homogenous oral pharmaceutical composition comprising a therapeutically effective amount of propiverine or one of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient with proper release profile manufactured by using reproducible high shear manufacturing processes.

An advantage of high-shear granulation is that the process is completed within a short period of time. It does, however, need to be carefully controlled as the formulation can quickly progress from under- to over-granulated.

Another object of the present invention relates to a pharmaceutical composition comprising propiverine and one or more pharmaceutically acceptable excipients, wherein the propiverine is in hydrochloride form. Another object of the present invention relates to a pharmaceutical composition comprising propiverine hydrochloride presenting homogenous behavior from the composition with at least one pH independent polymer to form a gel layer to present sustained release in the intestine region.

Another object of the present invention relates to a homogenous pharmaceutical composition comprising propiverine hydrochloride and one or more pharmaceutically acceptable excipient with proper pharmaceutical characteristics manufactured by using high shear granulation parameters as critical part of wet granulation method.

Detailed Description of the Invention

The present invention provides a pharmaceutical composition comprising propiverine hydrochloride and pharmaceutically acceptable excipients with pharmaceutical formulations comprising propiverine in solid dosage form.

In accordance with the present invention, the pharmaceutical tablet formulation comprising propiverine or its pharmaceutically acceptable salts thereof is composed of the granule prior to tablet compression of the population of granules.

The propiverine hydrochloride-containing particles of the present invention is easily incorporated into pharmaceutical dosage forms for oral administration to patients in need thereof.

The pharmaceutically acceptable excipient used in the methods of the present invention may be release modifying agents, a filler, a binder, a disintegrant, a lubricant, a solvent and a buffering agent or mixtures thereof.

Within the context of the present invention, the pharmaceutical composition comprises at least two release modifying polymers of different types of hydroxypropyl methylcellulose.

In a preferred embodiment, the pharmaceutical composition comprises at least a binder can be selected from hypromellose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. Preferably, the binder is povidone. In a preferred embodiment, the pharmaceutical composition comprising at least one disintegrant which can be selected from sodium carboxymethyl cellulose, sodium starch glycolate, crospovidone, com starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose. Preferably, the disintegrant is sodium carboxymethyl cellulose.

In a preferred embodiment, the pharmaceutical composition comprises at least one filler can be selected from the group consisting of dibasic calcium phosphate dihydrate, polysaccharides, microcrystalline cellulose, lactose and the like and mixtures thereof. Preferably, the filler is microcrystalline cellulose.

In a preferred embodiment, the pharmaceutical composition comprises at least one lubricant, selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof. Preferably, the lubricant is magnesium stearate.

In a preferred embodiment, the pharmaceutical composition comprises at least one buffering agent, selected from citric acid, tartaric acid, succinic acid, maleic acid, and fumaric acid. Preferably, the buffering agent is citric acid.

The buffering agent citric acid is known to be widely used in pharmaceutical formulations to adjust the pH of tablet matrices for colon-specific drug delivery. In a similar way, in the present invention, citric acid also affects positively to increase the release profile of propiverine with at least two pH independent polymer throughout the intestinal tract, regardless of the nature of the present propiverine salt, for example, salts of strong acids such as the hydrochloride.

In a preferred embodiment, the pharmaceutical composition comprises at least one solvent, selected from deionized water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, ethyl acetate, dimethylsulfoxide and their mixtures thereof. Preferably, the solvent is deionized water.

In yet another aspect of the embodiment, the granulation is high-shear granulation process.

The high-shear wet granulation process using high-shear granulator can be divided into main stages includes;

1. Preparation of binder solution

2. Mixing the powders separately 5

3. Binder addition or addition of granulating liquid. 4. Wetting of powder and nucleation (kneading)

5. Growth of granules and densification of the powder.

Manufacturing method is determined as wet granulation method considering, particularly wetting stage is important as the propiverine is a poor water-soluble drug. More particularly, granulation parameters should be optimized sensitively.

In one embodiment, the granulation process may result in enhanced granule consistency, improved workability of the final blend prior to solid oral dosage form.

In the details of manufacturing process, propiverine hydrochloride is first mixed with at least one pharmaceutically acceptable excipient in powder form.

In an embodiment of the present invention, manufacturing steps are: i. Propiverine hydrochloride, filler, disintegrant, a specified amount of release controlling agent(s) and glidant were mixed to obtain a uniform powder blend. ii. Granulation solution was prepared by dissolving the binder in the solvent. iii. The granulation solution prepared in step ii was added on the powder blend obtained in step i and granulation process was performed by using high-shear granulator. iv. Wet granules were dried to a specified moisture value and screened through 1.00 mm sieve. v. Pharmaceutically acceptable amount of lubricant was added on the granules obtained in step iv and mixed to obtain a uniform final blend. vi. Granules were used to get a pharmaceutically acceptable solid oral dosage forms.

The granulation solution was added to the powder mixture in step i with an optimized rate while the blend was subjected to high-shear granulation. The duration to give the granulation solution was 4-minute. Yet, the kneading time was optimized to maximum 1 minute to get a granule with proper characterization.

The drug product was analyzed to identify if it meets the quality attributes of international guidelines. The dissolution test was performed in 900 ml pH 7.2 phosphate buffer at 37°C±0.5°C with maintaining USP apparatus I (basket) at 100 rpm rotation speed.

The amount of dissolved active ingredient over time was determined by using a validated analytical HPLC method. Table 2: Results for Dissolution results of Formulation-I

The similarity factor f2 is the most common comparison index that is used to indicate the similarity of dissolution profiles between developed and reference drug products.

According to the Guideline on the Investigation of Bioequivalence, the similarity index f2 parameter should be higher than 50 to be similar with reference drug product. The f2 was calculated as per the information disclosed in guidelines, the result was 37.8 which means the release profiles were not similar within acceptable specifications.

Another analysis named as Uniformity of Dosage units was also performed to determine the assay of each tablet and to evaluate the homogeneity characterization of drug product.

The amount of active ingredient in each tablet was determined by using a validated analytical HPLC method.

Table 3: Results for Uniformity of Dosage units for Formulation-I

The results presented in Table-3 were not in line for each tablet which causes to calculate high relative standard deviation (RSD) in percentage.

Another embodiment to get a proper release profile and a more uniform drug product was considered to be designed. Therefore, an investigation was performed on the manufacturing and formulation details of Formulation-I.

The inventors surprisingly found that the common cause to get a drug product presenting slow release profile and unacceptable uniformity were related to the critical parameters during high- shear manufacturing.

The critical parameters in a high-shear manufacturing were the duration of giving the granulation solution, kneading time and the size of sieve. These are all very important to complete the wet granulation process successfully.

In the prior art as per the knowledge of wet granulation, the quality attributes of drug product depend on the size of final blend directly. However, in this manufacturing process the size of powder blend dried right after the kneading process was the most important application with an equation of both the duration to give granulation solution and kneading time, because as it was observed in Formulation-I the duration to give granulation solution and kneading time were not solely effective to obtain a qualified drug product.

Thus, the next embodiments were manufactured to perform a sieving process by using 0.80 and 0.60 mm sieves after drying the granule following kneading time. Using decreased size of sieve other than 0.60 mm brings out very fine granules which makes difficult to handle the powder for further processes. Next embodiments named as Formulation-II and Formulation-III by using 0.80 mm sieve respectively were manufactured according to the details presented below: i. Propiverine hydrochloride, filler, disintegrant, a specified amount of release controlling agent(s) and glidant were mixed to obtain a uniform powder blend. ii. Granulation solution was prepared by dissolving the binder in the solvent. iii. The granulation solution prepared in step ii was added on the powder blend obtained in step i and granulation process was performed by using high-shear granulator. iv. Wet granules were dried to a specified moisture value and screened through 0.80 mm sieve for Formulation-II and 0.60 mm sieve for Formulation-III. v. Pharmaceutically acceptable amount of lubricant was added on the granules obtained in step iv and mixed to obtain a uniform final blend. vi. Granules were used to get a pharmaceutically acceptable solid oral dosage forms.

The amount of dissolved active ingredient over time was determined by using a validated analytical HPLC method.

Table 4: Dissolution results for Formulation-II and Formulation-III

The f2 values were calculated as per the information disclosed in guidelines, the results were 55.2 and 60.6 for Formulation-II and Formulation-III respectively, which means the release profiles were similar within acceptable specifications.

Table 5: Results for Uniformity of Dosage units of Formulation II and Formulation-III

The results presented in Table-3 were in line for each tablet and relative standard deviation (RSD) in percentage is convenient which also demonstrates to be able to obtain pharmaceutical compositions with improved characteristics.

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

1. A homogenous pharmaceutical composition comprising propiverine hydrochloride and at least one pharmaceutically acceptable excipient, which is manufactured by wet granulation method wherein;

- the duration to give the granulation solution is 4-minute,

- kneading time is maximum 1 minute, and

- the size of sieve used after drying the granule following the kneading process is 0.60 mm or 0.80 mm.

2. A homogenous pharmaceutical composition according to claim 1, wherein the wet granulation method is performed by using high-shear granulator.

3. A homogenous pharmaceutical composition according to claim 1, wherein at least one pharmaceutically acceptable excipient is selected from release modifying agent(s), binder, disintegrant, filler, lubricant, buffering agent, solvent and mixtures thereof.

4. A homogenous pharmaceutical composition according to Claim 3, wherein the release modifying agents are at least two types of hydroxypropyl methyl cellulose.

5. A homogenous pharmaceutical composition according to claim 3, wherein the binder is selected from hypromellose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol and mixtures thereof.

6. A homogenous pharmaceutical composition according to claim 3, wherein the disintegrant is selected from sodium carboxymethyl cellulose, sodium starch glycolate, crospovidone, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose and mixtures thereof.

7. A homogenous pharmaceutical composition according to Claim 3, wherein the filler is selected from the group consisting of dibasic calcium phosphate dihydrate, polysaccharides, microcrystalline cellulose, lactose and the like and mixtures thereof.

8. A homogenous pharmaceutical composition according to Claim 3, wherein the lubricant is selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof.

9. A homogenous pharmaceutical composition according to Claim 3 , wherein the buffering agent is selected from citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid and mixtures thereof.

10. A homogenous pharmaceutical composition according to Claim 3, wherein the solvent is selected from deionized water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, ethyl acetate, dimethylsulfoxide and mixtures thereof.

11. The homogenous pharmaceutical composition according to any one of the preceding claims, wherein the high-shear granulation method comprises the steps of; i. Propiverine hydrochloride, filler, a specified amount of release controlling agent(s) and glidant are mixed to obtain a uniform powder blend. ii. Granulation solution is prepared by dissolving the binder in the solvent. iii. The granulation solution prepared in step ii is added on the powder blend obtained in step i and granulation process is performed by using high-shear granulator. iv. Wet granules are dried to a specified moisture value and screened through either 0.80 mm sieve or 0.60 mm sieve. v. Pharmaceutically acceptable amount of lubricant is added on the granules obtained in step iv and mixed to obtain a uniform final blend. vi. Granules are used to get a pharmaceutically acceptable solid oral dosage forms.

12. A homogenous pharmaceutical composition according to any one of the preceding claims, wherein the composition is compressed into a tablet dosage form.

13. A homogenous pharmaceutical composition according to any one of the claims 1-11, wherein the composition is filled into capsule dosage form.

14. A homogenous pharmaceutical composition according to any one of the preceding claims for use in the treatment of urinary incontinence and/or increased urinary frequency and urgency in patients with overactive bladder syndrome.