Field of the Invention

The present invention relates to a pharmaceutical form comprises a core, an acidic substance having a pKa value of less than 6.65 and at least one binder wherein the core is coated with an acidic substance having a pKa value of less than 6.65 and at least one binder. The pharmaceutical form may use in a form of tablet or capsule as an acidifying agent.

Background of the Invention

Controlled release formulations of pharmaceutical agents are an extremely large market in the pharmaceutical and medical fields. It is well known to those skilled in the art that controlled release formulations which are effective in maintaining therapeutic blood levels over extended periods to time result in optimal therapy. They not only reduce the frequency of dosing for enhanced patient convenience and compliance, but they also reduce the severity and frequency of side effects, as they maintain substantially constant blood levels and avoid fluctuations associated with conventional immediate release formulations administered three to four times a day. The rate and extent of drug release from most controlled release systems are influenced by the pH of the dissolution medium for drugs with pH-dependent solubility.

Especially, organic acids can be used to control the solubility of drug by changing the pH of internal environment of the pharmaceutical dosage forms.

In this invention, an alternative way of using an acidic substance having a pKa value of less than 6.65 directly in the formulation has been found. An acidic substance having a pKa value of less than 6.65 pellets were prepared.

Nowadays, pellets are playing a dominating role in the world of multiparticulate oral drug delivery. Pellets are defined as spherical, free-flowing granules with a narrow size distribution, typically varying between 500 and 1500 mm for pharmaceutical applications. These pellets have many advantages over single-unit dosage forms like controlled release. Pellets can reduce the risk of side effect due to high drug concentration, maximise drug absorption, spherical shape exhibits a good flow property with narrow size distribution. In this invention, the pharmaceutical form, the acidic substance having a pKa value of less than 6.65 pellet, was obtained. This may use in a form of tablet or capsule as an acidifying agent for controlled release formulations.

Thus, a pharmaceutical form has been developed that adjusts the pH of the medium and increases the stability of the formulation, helping to provide a good dissolution profile.

Detailed Description of the Invention

The main objective of the invention is to provide a pharmaceutical form. When this pharmaceutical form is used in a formulation, it helps the formulation to provide the desired dissolution profile and provide the desired stability.

Another object of the present invention is to provide a pharmaceutical form for controlled release formulations that is effective and does not interact with other excipients.

The term "core” will refer to a compact mass having a definite geometric shape such as tablets, granules, pellets, capsules.

The term ‘acidic substance having a pKa value of less than 6.65 pellet’ will refer to a coated core with acidic substance having a pKa value of less than 6.65 and at least one excipient. Also, it refers as pharmaceutical form in the present invention.

According to one embodiment of the present invention, a pharmaceutical form comprises a core, an acidic substance having a pKa value of less than 6.65 and at least one binder wherein the core is coated with an acidic substance having a pKa value of less than 6.65 and at least one binder. When the pharmaceutical form is used in the tablet or capsule formulation, the form is able to maintain a low pH and thus a sufficiently high drug solubility. By maintaining a low pH inside the pellets, a controlled drug release can be achieved.

According to one embodiment of the present invention, the pharmaceutical form, the acidic substance having a pKa value of less than 6.65 pellets, may use in a form of tablet or capsule as an acidifying agent.

According to one embodiment of the present invention, the core is neutral microcrystalline cellulose pellet or sugar pellet.

According to one embodiment of the present invention, the sugar pellet is sucrose or starch.

According to one embodiment of the present invention, an acidic substance having a pKa value of less than 6.65 is selected from the group comprising citric acid, tartaric acid, malic acid, maleic acid, succinic acid, ascorbic acid, fumaric acid, adipic acid or pharmaceutically acceptable salts thereof or a mixture of thereof.

Citric acid is a weak organic acid that has the chemical formula ObH _d O _? . It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in the metabolism of all aerobic organisms. Citric acid is used extensively for various compositions, pharmaceutical and otherwise. It is used widely as an acidifier, as a flavoring and a chelating agent.

According to one embodiment of the present invention, acidic substance having a pKa value of less than 6.65 is citric acid.

According to one embodiment of the present invention, preferably, the core is neutral microcrystalline cellulose pellet and the particle size of neutral microcrystalline cellulose pellet is between 0.3 mm and 0.7 mm. The neutral microcrystalline cellulose is a suitable core for the pharmaceutical form for having acceptable friability and high resistance to temperature.

According to one embodiment of the present invention, the amount of neutral microcrystalline cellulose pellets is between 10.0% and 40.0% by weight in the pharmaceutical form.

According to one embodiment of the present invention, the amount of neutral microcrystalline cellulose pellets is between 15.0% and 37.0% or between 20.0% and 35.0% by weight in the pharmaceutical form.

According to one embodiment of the present invention, the amount of citric acid is between 50.0% and 85.0% by weight in the pharmaceutical form.

According to one embodiment of the present invention, the amount of citric acid is between 55.0% and 80.0% or between 65.0% and 75.0% by weight in the pharmaceutical form.

According to one embodiment of the present invention, the core is free of active agent.

Suitable binder is selected from the group comprising polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol, pregelatinized starch, glucose, natural gums, sucrose, sodium alginate, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, gelatin, alginate, alginic acid, xanthan gum, hyaluronic acid, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof. According to one embodiment of the present invention, binder is polyviylpyrrolidone.

According to one embodiment of the present invention, the amount of the binder is between 0.5% and 10.0% by weight in the pharmaceutical form.

According to one embodiment of the present invention, the amount of the binder is between 1 .0% and 6.0% or between 1 .0% and 4.0% by weight in the pharmaceutical form.

According to one embodiment of the present invention, the pharmaceutical form further comprises at least anti-adhesive agent which is selected from the group comprising magnesium stearate, calcium stearate, talc or mixtures thereof.

According to one embodiment of the present invention, the core is coated with citric acid, polyvinylpyrrolidone and talc.

According to one embodiment of the present invention, the particle size of citric acid pellets is between 0.8 mm and 1.4 mm.

According to one embodiment of the present invention, the acidic substance having a pKa value of less than 6.65 pellets may be prepared, using standard techniques and manufacturing processes well known in the art, such as hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, spray drying and solvent evaporation.

According to one embodiment of the present invention, the acidic substance having a pKa value of less than 6.65 pellets are prepared with spraying by fluid bed granulator. In this way, it provides to obtain the desired homogeneous and stability form.

According to one embodiment of the present invention, the acidic substance having a pKa value of less than 6.65 pellets comprises;

10.0% - 40.0% by weight of neutral microcrystalline cellulose pellet,

- 0.5%- 10.0% by weight of polyvinylpyrrolidone,

- 50.0% - 85.0% by weight of acidic substance having a pKa value of less than 6.65,

1 .0% - 7.0% by weight of talc of the total the acidic substance having a pKa value of less than 6.65 pellets.

According to one embodiment of the present invention, the citric acid pellets comprises;

10.0% - 40.0% by weight of neutral microcrystalline cellulose pellet,

- 0.5%- 10.0% by weight of polyvinylpyrrolidone,

- 50.0% - 85.0% by weight of citric acid, 1 .0% - 7.0% by weight of talc of the total the citric acid pellets.

According to one embodiment of the present invention, the process for the preparation of acidic substance having a pKa value of less than 6.65 pellets comprises steps of:

Adding acidic substance having a pKa value of less than 6.65, polyvinylpyrrolidone and talc in pure water and obtained a suspension,

Spraying the suspension to neutral microcrystalline cellulose pellet for coating at fluid bed dryer,

Obtained round acidic substance having a pKa value of less than 6.65 pellets.

According to one embodiment of the present invention, the process for the preparation of citric acid pellets comprises steps of:

- Adding citric acid, polyvinylpyrrolidone and talc in pure water and obtained a suspension,

- Spraying the suspension to neutral microcrystalline cellulose pellet for coating at fluid bed dryer,

- Obtained round citric acid pellets.

According to one embodiment of the present invention, the said pharmaceutical form comprises citric acid to increasing the dissolution profile in weak acidic or basic pH values. The citric acid pellets led to a controlled release of an active agent (solubility of its dependent on the pH value), resulting from modulation of the microenvironmental pH throughout the dissolution period of 17 hours.

According to one embodiment of the present invention, an active agent may be propiverine or a pharmaceutically acceptable salt thereof or dabigatran or a pharmaceutically acceptable salt thereof.

Example 1 : Citric acid pellets Example 2: Citric acid pellets

Process for example 1 or 2;

- Adding citric acid, polyvinylpyrrolidone and talc in pure water and obtained a suspension,

- Spraying the suspension to neutral microcrystalline cellulose pellet for coating at fluid bed dryer,

- Obtained round citric acid pellets.

Example 3: Using the above described citric acid pellets in a capsule formulation Example 4: Using the above described citric acid pellets in a capsule formulation

Process for example 3 or 4;

First step; a) Adding citric acid, polyvinylpyrrolidone, lactose monohydrate and talc in a mixing isopropyl alcohol-water and then, obtained a suspension, b) Spraying the suspension to citric acid pellets for coating at fluid bed dryer and obtained rounded pellet 1 ,

Second step; c) Adding poly(methacrylic acid-co-methylmethacrylate) 1 :2 (Eudragit S 100), poly (methacrylic acid-co-methyl methacrylate) 1 :1 (Eudragit L 100), triethylcitrate and talc in a mixing isopropyl alcohol-water and then, obtained a suspension, d) Spraying the suspension to rounded pellet 1 for coating at fluid bed dryer and obtained rounded pellet 2,

Third step; e) Adding propiverine hydrochloride, citric acid, polyvinylpyrrolidone, talc and magnesium stearate in a mixing isopropyl alcohol-water and then, obtained a suspension, f) Spraying the suspension to rounded pellet 2 for coating at fluid bed dryer and obtained rounded pellet 3,

Fourth step; g) Adding ethyl acrylate or methyl methacrylate or a low content of methacrylic acid ester (Eudragit RS or Eudragit RL), poly(methacrylic acid-co-methylmethacrylate) 1 :2 (Eudragit S 100), triethylcitrate and talc in a mixing isopropyl alcohol-water-acetone and then, obtained a suspension, h) Spraying the suspension to granule 3 for coating at fluid bed dryer and obtained rounded pellet 4,

Fifth step; i) Adding poly(methacrylic acid-co-methylmethacrylate) 1 :2 (Eudragit S 100), triethylcitrate and talc in a mixing isopropyl alcohol-water and then, obtained a suspension, j) Spraying the suspension to rounded pellet 4 for coating at fluid bed dryer and obtained rounded pellet 5, k) Curing the rounded pellet 5,

Sixth step;

L) Mixing the dried rounded pellet 5 and talc, m) Filling the rounded pellets into capsule.