PROPIVERINE

Field of the Invention

The present invention relates to a novel sustained release solid pharmaceutical composition for oral administration comprising propiverine or a pharmaceutically acceptable salt thereof with at least one pH independent release controlling polymer for use in the treatment of urinary urgency, frequency and urge incontinence, all symptoms of overactive bladder syndrome.

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 that 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.

DD 106643 numbered patent is the basic patent that is first mentioned about propiverine and its salts.

EP 1435915 (Apogepha Arzneimittel GmbH) provides 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 USP buffer at pH 5.8 using a Ph. Eur. basket method at 100 rpm and 37°C.

W02006046560 (Taiho Pharmaceutical) provides 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) provides 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) discloses 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) provides 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) provides 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.) disclose 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) provides 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 Ilac San. A.§) provides 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 50.0% after nine hours and more than 85.0% after 24 hours as measured by USP Type I apparatus (basket) at 100 rpm, in 750 mL of 0.1 N hydrochloric acid for the first hour, subsequently in 750 mL USP buffer at pH 5.8 until nine hours, and subsequently in 750 mL of pH 6.8 USP buffer until 24 hours.

W02020101586A (Santa Farma Ilac San. A.§) provides a controlled release pharmaceutical compositions for oral administration comprising propiverine or a pharmaceutically acceptable salt thereof. This composition comprises 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 Methacrylic Acid - Methyl Methacrylate Copolymer (1:1) soluble starting from pH 6 and Methacrylic Acid - Ethyl Acrylate Copolymer (1: 1) Type A soluble starting from pH 5.5.

As pharmacokinetic point of view, the resorption rate is related with the half-life period 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.

After oral administration for immediate release of propiverine 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. For these reasons, 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 a pharmaceutical composition in the controlled release by using various pH-dependent and/or pH-independent polymers.

In the present invention, pharmaceutical composition comprising propiverine and one or more pharmaceutically acceptable excipients is developed in sustained release oral solid dosage form which extends the release of propiverine into 24 hours with a design of comprising at least one pH independent release controlling polymer(s). Summary of the Invention

The object of this invention is to develop a sustained release oral pharmaceutical composition comprising a therapeutically effective amount of propiverine or one of its pharmaceutically acceptable salts, at least two pH independent polymers and pharmaceutically acceptable excipients.

It is an object of the present invention is that a sustained release oral pharmaceutical composition comprising propiverine or one of its pharmaceutically acceptable salts, is used in the treatment of urinary incontinence and/or increased urinary frequency and urgency in patients with overactive bladder syndrome.

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 in the matrix with at least one pH independent polymer in a specified range of the total tablet weight to form a gel layer to present sustained release in the intestine region.

Another object of the present invention relates to a pharmaceutical composition comprising propiverine hydrochloride and one or more pharmaceutically acceptable excipients manufactured by using wet granulation method.

Another object of the present invention is related to a pharmaceutical composition comprising at least two pH independent polymers in the matrix located in the core.

Another object of the present invention relates to a pharmaceutical composition comprising a pH independent polymer having a viscosity of 70.000 to 140.000 cP in a 2% aqueous solution with an amount range of 8% to 10% by weight of the total tablet in the matrix located in the core.

Another object of the present invention relates to a pharmaceutical composition comprising a pH independent polymer having a viscosity of 80 to 120 cP in a 2% aqueous solution with an amount range of 2% to 4% by weight of the total tablet in the matrix located in the core. Detailed Description of the Invention

The present invention provides a pharmaceutical composition comprising propiverine hydrochloride and pharmaceutically acceptable excipients wherein at least two pH independent polymers is used to exhibit a sustained release profile of the drug.

Propiverine and its pharmaceutically acceptable salt thereof is a weakly basic drug an has particularly pH dependent solubility.

The term "sustained release" herein refers to any composition or dosage form which comprises an active drug and which is formulated to provide a longer duration of pharmacological response after administration of the dosage form than is ordinarily experienced after administration of a corresponding immediate release composition comprising the same drug in the same amount. Sustained release compositions include, inter alia, those compositions described elsewhere as "extended release", "delayed release", "controlled release", "prolonged release", "programmed release", "modified release", "time release" and/or "rate controlled" compositions or dosage forms.

In the preferred embodiments of the invention, sustained release compositions include a core comprising at least two pH independent polymers with different viscosities to overcome the pH dependent solubility of propiverine and its pharmaceutically acceptable salts thereof.

The solubility of pH independent release controlling polymer is independent of pH and hence its performance does not depend on the pH of the environment it encounters.

In the preferred embodiment of the present invention, the pH independent polymers are selected from the group comprising ethyl cellulose, cellulose acetate, vinyl acetate/vinyl chloride copolymers, acrylate/methacrylate copolymers, polyethylene oxide, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, karaya gum, acacia gum, tragacanth gum, locust bean gum, guar gum, methyl cellulose, beeswax, carnauba wax, cetyl alcohol, hydrogenated vegetable oils, and stearyl alcohol. Preferably, at least two pH independent polymers are different kinds of hydroxypropyl methylcellulose.

In the preferred embodiment of the present invention, at least one of the pH independent polymer is high viscosity hydroxypropyl methyl cellulose, and at least one of two pH independent polymers is low viscosity hydroxypropyl methyl cellulose to get desired dissolution profile in the sustained release dosage form. Hydroxypropyl methylcellulose (HPMC) is used to form swellable- soluble matrices. It hydrophilic and non-ionic, hence the matrices including them exhibit pH independent drug release profiles even though drug solubility is pH dependent. Thus, it is used to provide the release of a drug in a controlled manner. Viscosity grades of HPMC is important to get desired dissolution profile. The pores of high- viscosity HPMC block up quickly and inhibit further liquid uptake. This in turn leads to the formation of a turbid gel, which resists dilution and erosion, subsequently resulting in slower drug diffusion and release rate possess long side-chains are less mobile because of interaction with the gel. This increases the time taken for such drugs to diffuse through the gel structure. One proposed advantage of using a high-viscosity polymer is that, because of the rapid hydration and formation of a gel, it is likely to prevent dose dumping.

Many types of HPMC are identified by codes. For instance, the first part is a letter (E, F or K) relates to the degree of substitution. The K grades have a methoxy substitution of 19-24% and a hydroxypropyl substitution of 7-12%. F have a methoxy substitution of 27-30% and a hydroxypropyl substitution of 4.0- 7.5%. E grades have a methoxy substitution of 28-30% and a hydroxypropyl substitution of 7-12%. This first letter is followed by an indication of the viscosity of their aqueous 2% w/w gels at 20°C.

In the preferred embodiment of the present invention, the low viscosity matrix forming polymer is selected from the group comprising a hydroxypropyl methylcellulose selected from HPMC K100LV, HPMC E50LV, HPMC E5, HPMC E15LV or a combination of two or more thereof; and the high viscosity matrix forming polymer includes a hydroxypropyl methylcellulose selected from HPMC K4M, HPMC K15M, HPMC K100M, HPMC E4M and combinations of two or more thereof.

In a preferred embodiment of the present invention, low viscosity polymer has a viscosity within the range of 80 to 120 cP in 2% aqueous solution.

In a preferred embodiment of the present invention, high viscosity matrix forming polymer has a viscosity within the range of 70.000 to 140.000 cP in 2% aqueous solution.

In a preferred embodiment of the present invention, low viscosity polymer is present within the range of 8% to 10% by weight of the composition. In a preferred embodiment of the present invention, low viscosity polymer is present within the range of 2% to 4% by weight of the composition

The said invention is achieved by combining propiverine or one of its pharmaceutically acceptable salts with at least two pH independent polymers may further include one or more of other pharmaceutically acceptable excipients selected from, but not limited to, binder, diluent, lubricant, buffering agent and solvent selected as to be the most suitable ones with respect to the intended form of administration.

In a preferred embodiment, the pharmaceutical composition comprises at least a binder can be selected from hypromellose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. Preferably, the binder is sodium carboxymethyl cellulose, povidone or a mixture thereof, more preferably is a mixture thereof.

In a preferred embodiment, the pharmaceutical composition comprises at least one diluent can be selected from the group consisting of dibasic calcium phosphate dihydrate, polysaccharides, microcrystalline cellulose, lactose and the like and mixtures thereof. Preferably, the diluent 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 some embodiments of the present invention, a sustained release compositions are compressed into solid dosage form such as tablet, film-coated tablet, enteric-coated tablet, mini-tablet, granule, powder and capsule.

Three embodiments called Example 1, Example 2 and Example 3 in accordance with the present invention were designed with determined quantitative composition composed of pharmaceutically acceptable ingredients mentioned above. The prepared pharmaceutical compositions comprising propiverine hydrochloride, at least two pH independent polymers and at least one pharmaceutically acceptable excipient.

In Example 1, Example 2 and Example 3, pH independent polymers with different viscosity grades, were used within a specified range to adjust the viscosity range to get desired drug release profile. Moreover, propiverine hydrochloride and the excipients were also used in the specified range in all the examples. Examples were manufactured by using wet granulation method.

The proposed embodiments based on the invention provides a sustained release pharmaceutical composition wherein the amounts in w/w% by weight of the composition are as stated below:

Table 1: Quantitative Formula of Example 1, Example 2 and Example 3 Table 2: Viscosities of pH independent polymers

Detailed manufacturing steps are as presented below: i. Propiverine hydrochloride, Microcrystalline cellulose, Sodium carboxymethyl cellulose and the specified amount of low viscosity pH polymer were weighed, transferred into the high shear mixer through screening with a proper sieve and stirred, ii. Povidone was dissolved in a sufficient amount of deionized water till to dissolve completely, iii. The solution in Step (ii) was added into the powder blend prepared in Step (i) to perform granulation process, iv. The granule prepared in Step (iii) were dried in fluid bed dryer and shifted through a proper sieve, v. High viscosity polymer, Citric acid, Magnesium stearate and the rest of the low viscosity polymer were screened through a proper sieve and added to the granules prepared in Step (iv) and stirred, vi. Tablet compression was performed with the final blend in Step (v).

The dissolution conditions were designated considering the gastrointestinal pathway of orally applied dosage forms.

The first step of the dissolution test is performed in 0.1N HCI solution for 2 hours and then continues in 900 ml pH 6.8 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 HPLC.

Limited amount of propiverine is released in 2-hour duration with 0.1N HCI solution. Further, dissolution test was continued in pH 6.8 phosphate buffer with the conditions specified above. Table 3: Results of dissolution test performed at pH 6.8 phosphate buffer

A similarity factor Ϊ2 is the most common comparison index that is used to indicate the similarity of dissolution profiles between examples and reference drug product.

Table 4: f2 index of Example 1, Example 2 and Example 3 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.

Considering the f2 index of Example 1, Example 2 and Example 3, it is reported that the similarities between reference drug product with Example 2 and Example 3 are very good. In spite of that Example 1 is not similar to reference drug product. As a result, the present invention provides a pharmaceutical composition comprising propiverine hydrochloride and at least two pH independent release controlling polymer wherein one of the polymer is selected as low viscosity polymer within the range of from about to 80 to 120 cP in a 2% aqueous solution present in the range of 8% to 10% by weight of the total composition, and other pH independent polymer is selected as high viscosity polymer having viscosity within the range of 95.000 to 140.000 cP in a 2% aqueous solution present in the range of 2% to 4% by weight of the total composition to form matrix structure to get desired dissolution profile in the sustained release dosage form.

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.