WO2023080856A1

WO2023080856A1 - Enteric coated pharmaceutical composition of propiverine hydrochloride

Info

Publication number: WO2023080856A1
Application number: PCT/TR2021/051127
Authority: WO
Inventors: Erol KIRESEPI; Ersin Yildirim
Original assignee: Santa Farma Ilac Sanayi AS
Current assignee: Santa Farma Ilac Sanayi AS
Priority date: 2021-11-03
Filing date: 2021-11-03
Publication date: 2023-05-11
Anticipated expiration: 2024-05-03

Abstract

The present invention relates to an enteric coated sustained release pharmaceutical composition for oral administration comprising propiverine or a pharmaceutically acceptable salt thereof which wherein pharmaceutical composition has enteric coating comprising two release modifying agents with the ratio of 1:1 with an amount range of 3% to 5% by weight of the core tablet.

Description

ENTERIC COATED PHARMACEUTICAL COMPOSITION OF PROPIVERINE HYDROCHLORIDE

Field of the Invention

Background of the Invention

Propiverine is a benzylic acid derivative that is widely used for demonstrating to both anticholinergic agent and calcium-modulating properties to treat urinary incontinence, as well as frequency associated with detrusor over activity, such as neurogenic bladder and bladder irritation.

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 in the 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 relates to a prolonged-release pharmaceutical composition comprising 4 mg to 60 mg 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 0.1N 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 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 relates to a pharmaceutical composition by comprising a plurality of sustained- 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 sustained release coating disposed over the alkaline buffer layer. Enteric effect is provided by multiple coatings.

CN102579404A relates to 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 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 2007105229 relates to a novel sustained 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 relates to a sustained-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 relate 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 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.

EP3331502 relates to a sustained 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.

EP3331502 relates to a sustained release pharmaceutical composition comprising at least two pH dependent polymers in the core matrix and an enteric coating in an amount of the range between 0.5% to 2.5% by weight of core tablet wherein pH dependent polymers in the core matrix are Eudragit L-100 soluble starting from pH 6 (Methacrylic Acid - Methyl Methacrylate Copolymer (1:1)) and Eudragit L- 100-55 soluble starting from pH 5.5 (Methacrylic Acid - Ethyl Acrylate Copolymer (1: 1) Type A). Propiverine is widely used for demonstrating to both anticholinergic and calcium-modulating properties to treat of overactive bladder related with urinary urgency. Thus, it should be released in the intestinal tract.

Through passing the gastrointestinal tract, it is nearly completely absorbed and undergoes extensive first pass metabolism. Effects on urinary bladder smooth muscle cells are rapidly excreted into the urine.

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%. Whereas the mean absolute bioavailability is increased to 60.8 ± 17.3% and the gastrointestinal tract with maximal plasma concentrations is extended after 9 to 10 hours with developing sustained release dosage form of propiverine.

Especially in elderly patients and the main group with hypertonic functional states of the bladder, it is necessary to reduce the multiple administration per day by eliminating the intake intervals with the same or improved therapeutic effect.

The present invention relates to sustained release pharmaceutical composition comprising propiverine or a pharmaceutically acceptable salt thereof with enteric coating comprising two release modifying agents with specified ratio and amount in the composition to provide sustained release.

Summary of the Invention

The object of this invention is to develop an enteric coated sustained release pharmaceutical composition comprising therapeutically effective amount of propiverine or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient.

Another object of the present invention relates to an enteric coated sustained release pharmaceutical composition comprising propiverine and one or more pharmaceutically acceptable excipients, wherein the propiverine is in hydrochloride form.

Another object of the present invention is to provide a preparation method of a pharmaceutical composition herein disclosed can be manufactured into oral solid dosage forms, such as tablet, capsule, granule and powder. Another object of the present invention relates to an oral dosage form in the form of tablet comprising propiverine hydrochloride wherein the release of active ingredient is sustained by using at least one release modifying agent in the film coating layer.

A further object of the present invention is related to an enteric coated sustained release pharmaceutical composition comprising propiverine hydrochloride coated with acceptable two release modifying agents and optionally with other pharmaceutically acceptable excipients wherein the ratio of at least one release modifying agents is 1 : 1 in the enteric coating layer that presents in a weight ratio to the core tablet within the range of from 3% to 5% to achieve sustained release dissolution profile.

Detailed Description of the Invention

The present invention provides an enteric coated sustained release pharmaceutical composition comprising propiverine hydrochloride in the core and an enteric coating is used to coat the core comprising two release modifying agents and optionally with other pharmaceutically acceptable excipients.

The term “sustained release” refers to a pharmaceutical dosage form which releases the active ingredient(s) into the body at a programmed release rate over a specified period of time to prolong the release time period. Thus, it can reduce the dosing frequency by maintaining therapeutically effective drug concentrations over a prolonged period of time and improve the patient compliance. Preferably, the present invention provides a release of the active ingredient at least up to 12 hours.

Sustained release by adjusting the speed of drug release can keep the concentration of the drug at a constant level in the blood or target tissue. It is one of the methods to achieve sustained drug release is by preventing drug molecules from entering completely the aqueous environment for a manageable period of time.

Propiverine is typical anticholinergic agent, and also acts as a calcium channel antagonist, used for the treatment of urinary incontinence and/or increased urinary frequency and urgency in patients with overactive bladder syndrome and should be released in the intestinal tract. However, it has pH dependent solubility and have limited availability in the small intestine. According to the prior art documents, propiverine hydrochloride exhibits various release profiles in different pH environments. In acidic medium up to pH 5.8 it can freely soluble, but it shows slightly solubility in alkaline pH or over pH 6.6.

Thus, in the preferred embodiment, sustained release of prepared pharmaceutical composition is provided to modify the solubility and dissolution profile of propiverine hydrochloride for different periods of time during its passage through the gastrointestinal tract by using two different release modifying agents.

In the preferred embodiment of the present invention, the release modifying agents are may include, but are not limited to, ethyl cellulose, cellulose acetate, polymethylmethacrylate copolymer, polyvinyl acetate and acetate -polyvinyl pyrrolidone copolymer. Preferably, the release modifying agent is polymethacrylate copolymer.

Polymethacrylate copolymers are widely used in oral capsule and tablet formulations as filmforming agents for provide sustained release formulations.

Depending on the based on functional groups of the type of polymer like cationic, anionic and neutal polymer of dimethylaminoethyl methacrylates, methacrylic acid esters in varying ratios, films of different solubility characteristics can be produced.

According to the literature knowledge, the ammonium groups are presents as salts and give rise to pH-independent permeability of the polymers. Thus in the preferred embodiment, at least one ammonio methacrylate copolymers derived from ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups are selected and used in combination at specified ratio to provide desired colon-specific delivery of propiverine in buffer solutions by depending on swelling behavior in the media mimicking different parts of gastrointestinal tract.

In the preferred embodiment of the present invention, the ammonio methacrylate copolymers may include, but are not limited to the group consisting of ammonio methacrylate copolymer, Type B, USP; ammonio methacrylate copolymer, Type A, USP; methacrylic acid copolymer, Type B, USP; methacrylic acid copolymer, Type A, USP, and the mixture thereof.

Preferably, chemical name of selected ammonio methacrylate copolymer Type A is Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1.

Preferably, chemical name of selected ammonio methacrylate copolymer Type B is Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) l:2:0.2. Both of described ammonio methacrylate copolymer are insoluble neither in acidic nor alkaline physiological pH solutions, but permeable in digestive fluids and enable sustained time release of the active ingredient by pH-independent swelling.

However, ammonio methacrylate copolymer Type B has low permeability in the dissolution media as compared with ammonio methacrylate copolymer Type A. Thus, in the preferred embodiment selected polymethacrylate copolymers are used together in various proportions to achieve the customized release profile of propiverine hydrochloride.

According to the present invention, enteric coating is present in an amount of in a range from 3% to 13% by the total tablet weight to provide sustained release in vitro dissolution profile.

In a preferred embodiment of the present invention is to provide a pharmaceutical composition for oral administration. Suitable solid oral dosage forms are selected from the group comprising tablet, capsule, granule and powder. Preferably, the solid oral dosage form is tablet.

In a more preferred embodiment of the present invention, the prepared pharmaceutical composition comprising propiverine hydrochloride is formulated in a single dosage form for oral administration within enteric coating.

The embodiment in accordance with the present invention is designed with adjusted quantitative composition composed of film coating layer ingredients mentioned above by using wet granulation process.

In a preferred embodiment, the quantitative and qualitative formulation of the core comprising propiverine hydrochloride and at least one excipients is kept the same.

In another preferred embodiment, the enteric coating layer consists of a mixture of ammonio methacrylate copolymer Type A and ammonio methacrylate copolymer Type B in a ratio of 1 : 1 and 2:1.

The proposed embodiment based on the invention, enteric coating layer composition is as stated in the Table 1 below: Table 1: Unit formula of enteric coating layer

The detailed manufacturing steps for enteric coating solution are presented below: i. Acetone, isopropyl alcohol and deionized water are weighed and stirred, ii. Ammonio methacrylate copolymer Type A, ammonio methacrylate copolymer Type B are weighed and added to the specified amount of the preparation in Step (i), iii. Triethyl citrate and talc are weighed and added to the remaining amount of the preparation in Step (i), iv. The preparation in Step (iii) is slowly added to the preparation in Step (ii), v. The final blend is filtered through a proper filter. The prepared core pharmaceutical oral dosage form comprising propiverine hydrochloride and other pharmaceutical excipients are coated with prepared enteric coating solution comprising different amounts of ammonio methacrylate copolymer Type A and ammonio methacrylate copolymer Type B.

The embodiments for the different ratios of release modifying agents in the enteric coating identified as Example 1 and Example 2 are given in the Table 2 below.

Table 2: Different ratios of release modifying agents in enteric coating solution

Further, different amounts of enteric coating layer are investigated to evaluate sustained release dissolution profile. Based on this query, other embodiments identified as;

Example 1.1, Example 1.2, Example 1.3, Example 1.4 by using Example 1 in ratio of 2:1 as dedicated in Table 1 were designed.

Example 2.1 and Example 2.2 by using Example 2 in ratio of 1:1 as dedicated in Table 1 were designed.

Details are given in the Table 2 below wherein the amount of enteric coating layer is presented in weight ratios within the ranges from 3% to 13%.

Table 3: Examples for different amounts of enteric coating layer

According to the preferred embodiment, all Examples were subjected to in vitro dissolution profiles.

The conditions of dissolution study are set by studying the pharmacokinetic properties and targeted tissue of absorption. Thus, propiverine hydrochloride having in vitro release, measured in 750 ml of 0.1N hydrochloric acid for 1 hour and subsequently measured in 750 ml USP buffer at pH = 5.8 for 12 hours using a Ph. Eur. Basket method at 100 rpm and 37°C±0.5°C.

The dissolution study was conducted in 0.1N HC1 at first hour to verify the release pattern of the enteric coated propiverine hydrochloride in acidic pH, and followed with pH 5.8 buffer to monitor a sustained release pattern in the intestine.

The amount of dissolved active ingredient over time was determined by HPLC.

Table 4: Comparative dissolution profiles of all Examples at 0.1N HC1 for 1 hour and later pH

5.8 12 hours in total

According to the given results, using higher amount of the Ammonio methacrylate copolymer Type A as release modifying agent in the enteric coating layer which was applied in amounts between 7%-9% is the reason for the decrease of penetration of drug release due to polymer swelling and then blocking the pathway of the medium and the drug for the first hour.

The examples identified as Example 2.1 and Example 2.2 present a similar release profile to reference drug product in the first and the other time points of in vitro dissolution study.

Besides the sustained drug release in the stomach, to obtain extended release over 12 hours is also other object in this present invention. Except the Example 2.1 and Example 2.2, the rest all Examples showed faster dissolution than the reference drug product for 12 hours.

The proper dissolution profile was obtained, when the ratio of ammonio methacrylate copolymer Type A and ammonio methacrylate copolymer Type B was 1:1 and enteric coating layer was in an amount of the range between 5% to 3% by weight of the core tablet, wherein the combined release modifying agents were promoted a faster drug release than other Examples but similar to reference drug product in the first hour, and a sustained release through 12 hours, in which the proper coating resulted in effective gastric resistance by gradually swelling over time to control the release of drug in the stomach.

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. An enteric coated sustained release pharmaceutical composition comprising propiverine or a pharmaceutically acceptable salt thereof wherein the enteric coating comprises two release modifying agents with the ratio of 1:1 with an amount range of between 3% to 5% by weight of the core tablet.

2. An enteric coated sustained release pharmaceutical composition according to Claim 1, comprises propiverine hydrochloride equivalent to 5 mg to 45 mg propiverine.

3. An enteric coated sustained release pharmaceutical composition according to any one of the preceding claims, wherein two release modifying agents are selected from ethyl cellulose, cellulose acetate, polymethylmethacrylate copolymer, polyvinyl acetate and acetate-polyvinyl pyrrolidone copolymer.

4. An enteric coated sustained release composition according to any one of the preceding claims, wherein at least one releasing modifying agent is ammonio methacrylate copolymer Type A.

5. An enteric coated sustained release composition according to any one of the preceding claims, wherein at least one releasing modifying agent is ammonio methacrylate copolymer Type B.

6. An enteric coated sustained release composition according to any one of the preceding claims, wherein the composition comprises ammonio methacrylate copolymer Type A and ammonio methacrylate copolymer Type B as two release modifying agents.

7. An enteric coated sustained release 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.