EP4061369A1 - A pharmaceutical form comprising acidic substance - Google Patents

A pharmaceutical form comprising acidic substance

Info

Publication number
EP4061369A1
EP4061369A1 EP20889151.5A EP20889151A EP4061369A1 EP 4061369 A1 EP4061369 A1 EP 4061369A1 EP 20889151 A EP20889151 A EP 20889151A EP 4061369 A1 EP4061369 A1 EP 4061369A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical form
form according
weight
acid
citric acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20889151.5A
Other languages
German (de)
French (fr)
Other versions
EP4061369A4 (en
Inventor
Fatih Sunel
Gulcin TOK
Selin KOKSAL UZUN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanovel Ilac Sanayi ve Ticaret AS
Original Assignee
Sanovel Ilac Sanayi ve Ticaret AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from TR2019/18013A external-priority patent/TR201918013A2/en
Application filed by Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Publication of EP4061369A1 publication Critical patent/EP4061369A1/en
Publication of EP4061369A4 publication Critical patent/EP4061369A4/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder

Definitions

  • the present invention relates to a pharmaceutical form
  • 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.
  • 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.
  • organic acids can be used to control the solubility of drug by changing the pH of internal environment of the pharmaceutical dosage forms.
  • 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.
  • 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.
  • the main objective of the invention is to provide a pharmaceutical form.
  • this 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.
  • core will refer to a compact mass having a definite geometric shape such as tablets, granules, pellets, capsules.
  • 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.
  • 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, 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.
  • the core is neutral microcrystalline cellulose pellet or sugar pellet.
  • the sugar pellet is sucrose or starch.
  • 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.
  • acidic substance having a pKa value of less than 6.65 is citric acid.
  • 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.
  • the amount of neutral microcrystalline cellulose pellets is between 10.0% and 40.0% by weight in the pharmaceutical form.
  • 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.
  • the amount of citric acid is between 50.0% and 85.0% by weight in the pharmaceutical form.
  • 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.
  • 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.
  • binder is polyviylpyrrolidone.
  • the amount of the binder is between 0.5% and 10.0% by weight in the pharmaceutical form.
  • 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.
  • 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.
  • the core is coated with citric acid, polyvinylpyrrolidone and talc.
  • the particle size of citric acid pellets is between 0.8 mm and 1.4 mm.
  • 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.
  • 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.
  • the acidic substance having a pKa value of less than 6.65 pellets comprises;
  • the citric acid pellets comprises;
  • citric acid pellets - 50.0% - 85.0% by weight of citric acid, 1 .0% - 7.0% by weight of talc of the total the citric acid pellets.
  • the process for the preparation of acidic substance having a pKa value of less than 6.65 pellets comprises steps of:
  • Obtained round acidic substance having a pKa value of less than 6.65 pellets.
  • the process for the preparation of citric acid pellets comprises steps of:
  • 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.
  • 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
  • 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
  • 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,

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

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.

Description

A PHARMACEUTICAL FORM COMPRISING ACIDIC SUBSTANCE
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 ObHdO?. 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.

Claims

1 . A pharmaceutical form comprising 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 citric acid and at least one binder.
2. The pharmaceutical form according to claim 1 , wherein the core is neutral microcrystalline cellulose pellet or sugar pellet.
3. The pharmaceutical form according to claim 2, wherein 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.
4. The pharmaceutical form according to claim 3, wherein the amount of neutral microcrystalline cellulose pellets is between 10.0% and 40.0% by weight in the pharmaceutical form.
5. The pharmaceutical form according to claim 1 , wherein the 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.
6. The pharmaceutical form according to claim 5, wherein the acidic substance having a pKa value of less than 6.65 is citric acid.
7. The pharmaceutical form according to claim 6, wherein the amount of citric acid is between 50.0% and 85.0% by weight in the pharmaceutical form.
8. The pharmaceutical form according to claim 1 , wherein the core is free of active agent.
9. The pharmaceutical form according to claim 1 , wherein binder is selected from the group comprising polyvinylpyrrolidone, sodium carboxymethyl cellulose, polyethylene glycol, hydroxypropyl methylcellulose, 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.
10. The pharmaceutical form according to claim 9, wherein binder is polyviylpyrrolidone.
11. The pharmaceutical form according to claim 9, wherein the amount of the binder is between 0.5% and 10.0% by weight in the pharmaceutical form.
12. The pharmaceutical form according to claim 1 , further comprising at least anti adhesive agent which is selected from the group comprising magnesium stearate, calcium stearate, talc or mixtures thereof.
13. The pharmaceutical form according to claim 1 , comprising;
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.
14. The pharmaceutical form according to claim 6, comprising;
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 total the citric acid pellets.
15. A process for the preparation of a pharmaceutical form according to claim 14, wherein the process further comprising 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.
EP20889151.5A 2019-11-19 2020-10-27 A pharmaceutical form comprising acidic substance Pending EP4061369A4 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
TR2019/18013A TR201918013A2 (en) 2019-11-19 2019-11-19 PELLET COMPOSITION CONTAINING PROPIVERIN OR A PHARMACEUTICALLY ACCEPTABLE SALT OF PROPIVERIN
TR2020/16210A TR202016210A2 (en) 2019-11-19 2020-10-12 Pharmaceutical form containing acidic substance
PCT/TR2020/051001 WO2021101483A1 (en) 2019-11-19 2020-10-27 A pharmaceutical form comprising acidic substance

Publications (2)

Publication Number Publication Date
EP4061369A1 true EP4061369A1 (en) 2022-09-28
EP4061369A4 EP4061369A4 (en) 2024-04-10

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EP20889151.5A Pending EP4061369A4 (en) 2019-11-19 2020-10-27 A pharmaceutical form comprising acidic substance

Country Status (3)

Country Link
EP (1) EP4061369A4 (en)
CA (1) CA3162409A1 (en)
WO (1) WO2021101483A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100596276C (en) 2005-01-26 2010-03-31 杭州民生药业有限公司 Vinpocetine sustained-release capsules and preparation method thereof
CN102579404A (en) 2012-01-17 2012-07-18 广州科的信医药技术有限公司 Sustained-release capsule containing propiverine hydrochloride and preparation method of sustained-release capsule
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