WO2021145831A1 - Compositions pharmaceutiques comprenant du tadalafil et des excipients appropriés - Google Patents

Compositions pharmaceutiques comprenant du tadalafil et des excipients appropriés Download PDF

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Publication number
WO2021145831A1
WO2021145831A1 PCT/TR2020/050030 TR2020050030W WO2021145831A1 WO 2021145831 A1 WO2021145831 A1 WO 2021145831A1 TR 2020050030 W TR2020050030 W TR 2020050030W WO 2021145831 A1 WO2021145831 A1 WO 2021145831A1
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WO
WIPO (PCT)
Prior art keywords
tadalafil
tablet
pulmonary
granules
pharmaceutical
Prior art date
Application number
PCT/TR2020/050030
Other languages
English (en)
Inventor
Ayşe Figen ONUK GÖREN
Başak ACAR KARAKÖY
Hakan Gürpinar
Koray YILMAZ
Asiye SEZGİN
Gizem ALKAN
Original Assignee
Pharmacti̇ve İlaç Sanayi̇ Ve Ti̇caret A.Ş.
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
Application filed by Pharmacti̇ve İlaç Sanayi̇ Ve Ti̇caret A.Ş. filed Critical Pharmacti̇ve İlaç Sanayi̇ Ve Ti̇caret A.Ş.
Priority to PCT/TR2020/050030 priority Critical patent/WO2021145831A1/fr
Publication of WO2021145831A1 publication Critical patent/WO2021145831A1/fr

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems

Definitions

  • the present invention relates to the preperation of pharmaceutical compositions comprising tadalafil in the treatment of sexual dysfunction and pulmonary arterial hypertension, having an improved manufacturing process by using wet granulation method.
  • Phosphodiesterase-5 (PDE5) inhibiting substances are used for the treatment of erectile dysfunction and also pulmonary hypertension.
  • Tadalafil is a member of phosphodiesterase inhibitor drugs.
  • Tadalafil has a chemical name as (6R,12aR)-6-(l,3-Benzodioxol-5-yl)-2-methyl- 2,3,6,7,12,12a-hexahydropyrazino[r,2':l,6]pyrido[3,4-b]indole-l,4-dione and its chemical structure is shown in the Figure I.
  • Tadalafil has molecular weight of 389.404 g/mol, is a white crystalline powder.
  • Tadalafil has high therapeutic value in the treatment of sexual dysfunctions. It is also useful for the treatment of cardiac, pulmonary and vascular-related conditions.
  • Sexual dysfunction is a clinical problem which can affect both males and females.
  • the causes of sexual dysfunction may be both organic and psychological.
  • Organic reasons of sexual dysfunction are typically caused by vascular diseases, such as associated with hypertension / diabetes mellitus.
  • Physiological factors may be fear, performance anxiety and interpersonal conflict.
  • Pulmonary hypertension is a type of high blood pressure that affects the arteries in the lungs and the right side of your heart. Pulmonary hypertension is also called “Pulmonary Arterial Hypertension (PAH)”. Pulmonary hypertension is a disease characterized by increased pulmonary artery pressure and pulmonary vascular resistance.
  • PAH Pulmonary Arterial Hypertension
  • Adcirca(Tadalafil) is a trademark of Eli Lilly. Adcirca is used for pulmonary arterial hypertension. Adcirca composition: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.
  • Tadalafil is a selective Phosphodiesterase-5 inhibitor that have vasodilatory and antiproliferative effects on the pulmonary artery. It is evaluated the safety and efficacy of oral tadalafil in children with pulmonary arterial hypertension in a study. Tadalafil suspension was administrated at 1 mg/kg daily for all patients. Oral tadalafil was administered easily and tolerated well and improved mean pulmonary artery pressure (MPAP) in children with pulmonary arterial hypertension, oral tadalafil may be more effective and safer compared to sildenafil in the treatment of pulmonary arterial hypertension.
  • MPAP mean pulmonary artery pressure
  • US 2006/0148693 relates to a pharmaceutical composition comprises pulmonary surfactant and a phosphodiesterase-5 inhibitor to prevent/reduce the onset of symptoms of a disease in which pulmonary surfactant malfunction and/or phosphodiesterase-5 activity is detrimental.
  • WO 2014/125352 relates to a pharmaceutical composition comprises tadalafil or its salt, and excipients for treating sexual dysfunction, benign prostatic hyperplasia and/or pulmonary hypertension.
  • Patent application relates to a process for preparation of pharmaceutical compositions comprising tadalafil or a pharmaceutically acceptable salt thereof.
  • WO 2014/209022 relates to a chewable tablet, comprises granules comprising tadalafil, disintegrant e.g. sodium starch glycolate, carboxymethyl cellulose calcium and starch, and additive, for treating erectile dysfunction and pulmonary arterial hypertension.
  • the invention relates to a chewable tablet comprising granules comprising tadalafil; granules having a specific particle size and density prepared by a wet granulation.
  • the present invention relates to the preparation of pharmaceutical compositions comprising tadalafil from 2.5 mg to 20 mg in a unit dosage form for treating sexual dysfunction and tadalafil from 20 mg to 40 mg in a unit dosage form pulmonary arterial hypertension.
  • the present invention relates to the preparation of pharmaceutical compositions comprising tadalafil from 2.5 mg to 40 mg in a unit dosage form, wherein process including non aqueous wet granulation method.
  • the present invention relates to the preparation of pharmaceutical compositions comprising tadalafil from 2.5 mg to 20 mg in a unit dosage form, wherein process including wet granulation method.
  • the present invention relates to the preparation of pharmaceutical compositions comprising tadalafil from 20 mg to 40 mg in a unit dosage form, wherein process including wet granulation method.
  • aqueous (water) or non-aqueous (organic) solvents are used in wet granulation method.
  • the present invention relates to the preparation of pharmaceutical compositions comprising tadalafil from 2.5 mg to 20 mg in a unit dosage form, wherein process including non- aqueous(organic) solvents in wet granulation method.
  • the present invention relates to the preparation of pharmaceutical compositions comprising tadalafil from 20 mg to 40 mg in a unit dosage form, wherein process including non- aqueous(organic) solvents in wet granulation method.
  • Patent protection is valid for active pharmaceutical ingredient(Tadalafil) materials, wherein at least 90% of the particles have a particle size of less than about 40 microns (D90 ⁇ 40m).
  • the invitro profile similar to the reference product and thus the bioequivalent product can not be obtained. Therefore, API needs to be provided in a specific PSD range, which makes the procurement process difficult and increases the supplier cost in producing micronised Tadalafil.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising tadalafil from 2.5 mg to 20 mg in a unit dosage form for the treatment of sexual dysfunction, wherein at least 90% of the particles have a particle size of more than about 40 microns.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising tadalafil from 20 mg to 40 mg in a unit dosage form for the treatment of pulmonary arterial hypertension, wherein at least 90% of the particles have a particle size of more than about 40 microns.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising tadalafil from 2.5 mg to 40 mg in a unit dosage form and at least two excipients for dispersion step, wherein at least 90% of the particles have a particle size of more than about 40 microns.
  • the present invention provides a pharmaceutical composition comprising tadalafil from 2.5 mg to 40 mg in a unit dosage form, DMSO (Dimethyl sulfoxide) and SLS (Sodium laurilsulfate) can be used in dispersion step in wet granulation process.
  • DMSO Dimethyl sulfoxide
  • SLS Sodium laurilsulfate
  • the present invention provides a pharmaceutical composition comprising tadalafil from 2.5 mg to 40 mg in a unit dosage form, bioequivalent results obtained using prescribed method of formulation.
  • the present invention provides a pharmaceutical composition for use in a method of treating sexual dysfunction in a patient in need thereof, including male erectile dysfunction.
  • the pulmonary hypertension comprises pulmonary arterial hypertension (PAH), including but not limited to idiopathic PAH, familial PAH or PAH associated with another disease or condition.
  • PAH at baseline is of WHO Class I, II, III or IV.
  • Treating of pulmonary arterial hypertension can vary depending on the particular pulmonary hypertension condition to be treated such as the severity of the condition, body weight and other parameters of the individual subject, and can be readily established without undue experimentation by the physician or clinician based on the disclosure.
  • oral dosage forms can be used for pharmaceutical compositions comprising tadalafil.
  • Some common non-limiting examples of oral dosage forms include pills, tablets, capsules, wafers, pellets, or caplets.
  • the release rate of the dosage form comprising active ingredient as Tadalafil is partially or completely dependent on the usage of SLS in the present embodiment. Being a BCS classs II molecule the bioavailability of the dosage form may have significant impact in using a conventional surfactant like SLS.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising tadalafil or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
  • Tadalafil in the present product does not requires a defined PSD range. So it will provide a significant advantage in the screening process of Tadalafil from different suppliers in a wide portfolio and also advantage in providing at a less cost.
  • the present invention provides pharmaceutical composition comprising tadalafil from 2.5 mg to 40 mg in a unit dosage form and relevant excipients, characterized by i) A simple and exclusive manufacturing process ii) Bioequivalent to Reference product of Adcirca iii) Stable formulation, Dispersing Tadalafil and SLS in DMSO before granulation ensures uniform distribution of Tadalafil throughout the granules. Uniform distribution of Surfactant (SLS) will minimise variation in drug release.
  • the present invention provides pharmaceutical compositions comprising tadalafil from 2.5 mg to 40 mg in a unit dosage form reduces the dosing frequency based on the patient severity or as prescribed to the patient.
  • wet granulation method of manufacturing process can be used according to Tadalafil’ s physical and chemical properties. Excipients can be selected according to environment of process.
  • the formulation according to the present inventions may be in the form of a tablet, dragee, capsule, caplet, orally-disintegrating tablet, film-coated tablet, enteric tablet, buccal tablet, sublingual tablet, chewable tablet, effervescent tablet, slow-release tablet, rapid-release tablet, modified-release tablet, delayed-release tablet, prolonged- release tablet, controlled-release tablet and similar solid oral dosage forms.
  • the preferred dosage form according to the present invention is the solid dosage form, preferably a tablet form.
  • Effective or “therapeutically effective” amount of a drug or pharmacologically active agent means an amount of the drug or agent that is nontoxic and sufficient to provide the desired effect, e.g., pulmonary arterial hypertension (PAH).
  • PAH pulmonary arterial hypertension
  • treatment means any treatment of a disease or condition in a subject, such as a mammal, including: 1) preventing or protecting against the disease or condition, that is, causing the clinical symptoms not to develop; 2) inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; and/or 3) relieving the disease or condition that is, causing the regression of clinical symptoms.
  • D90 the particle size of Figure (I) is commonly referred to, and is herein, as the "D90.”
  • D90 > 40m means that at least 90% of the particles have a particle size of more than 40 microns.
  • composition comprising tadalafil can be used for the treatment of sexual dysfunction such as male erectile dysfunction and benign prostatic hyperplasia.
  • pulmonary hypertension means herein comprising different forms of pulmonary hypertension.
  • Nonlimiting examples, which may be mentioned in this connection are idiopathic pulmonary arterial hypertension; familial pulmonary arterial hypertension; pulmonary arterial hypertension associated with collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, HIV infection, drugs or toxins; pulmonary hypertension associated with thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy; pulmonary arterial hypertension associated with pulmonary capillary hemangiomatosis; persistent pulmonary hypertension of the newborn; pulmonary hypertension associated with chronic obstructive pulmonary disease, interstitial lung disease, hypoxia driven alveolar hypoventilation disorders, hypoxia driven sleep-disordered breathing or chronic exposure to high altitude; pulmonary hypertension associated with development abnormalities; and pulmonary hypertension due to thromboembolic obstruction
  • composition of the present inventions may comprise one or more pharmaceutically acceptable excipient(s).
  • Pharmaceutically acceptable excipients comprise, but are not limited to, fillers, disintegrants, binders, lubricants, glidants, sweeteners, aromatic agents, preservatives, coloring agents, and the mixtures thereof, to facilitate the physical formulation of various dosage forms like orally disintegrating tablets, chewable tablets and suspensions (including dry powders or granules for suspension).
  • Surfactants can be selected from the group, but are not limited to, polyoxyethylene hardened castor oil, glyceryl monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, polyoxyethylene polyoxypropylene block copolymers, polysorbates 80, sodium laurylsulfate (SLS), macrogols, sucrose esters of fatty acids and other materials known to one of ordinary skill in the art.
  • a preferred surfactant is Sodium Lauryl Sulfate (SLS).
  • a mixture of surfactants may also be used.
  • Example 1 Tadalafil 20 mg film coated tablet
  • Example 2 Tadalafil 40 mg film coated tablet Procedure for composition comprising tadalafil 40 mg tablet;
  • HSM High Shear Mixer
  • Granules are lubricated with Magnesium Stearate.
  • Powder was compressed in to tablet with specified punches.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une composition pharmaceutique comprenant du tadalafil à hauteur de 2,5 mg à 40 mg sous une forme posologique unitaire et au moins deux excipients pour l'étape de dispersion, au moins 90 % des particules ayant une taille de particule supérieure à environ 40 microns. La présente invention concerne également un procédé de granulation par voie humide.
PCT/TR2020/050030 2020-01-16 2020-01-16 Compositions pharmaceutiques comprenant du tadalafil et des excipients appropriés WO2021145831A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/TR2020/050030 WO2021145831A1 (fr) 2020-01-16 2020-01-16 Compositions pharmaceutiques comprenant du tadalafil et des excipients appropriés

Applications Claiming Priority (1)

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PCT/TR2020/050030 WO2021145831A1 (fr) 2020-01-16 2020-01-16 Compositions pharmaceutiques comprenant du tadalafil et des excipients appropriés

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WO2021145831A1 true WO2021145831A1 (fr) 2021-07-22

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1875914A1 (fr) * 2006-07-07 2008-01-09 Teva Pharmaceutical Industries Ltd. Les compositions solides comprenant tadalafil et au moins d'un agent de support
WO2012085927A2 (fr) * 2010-12-02 2012-06-28 Mylan Laboratories, Limited Compositions de tadalafil
WO2018142189A1 (fr) * 2017-02-02 2018-08-09 Dukebox Sp. Z O. O. Procédé de fabrication d'une suspension de nanoparticules de tadalafil ou de citrate de sildénafil
CN109528675A (zh) * 2018-12-31 2019-03-29 杭州康本医药科技有限公司 一种他达拉非肠溶片剂及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1875914A1 (fr) * 2006-07-07 2008-01-09 Teva Pharmaceutical Industries Ltd. Les compositions solides comprenant tadalafil et au moins d'un agent de support
WO2012085927A2 (fr) * 2010-12-02 2012-06-28 Mylan Laboratories, Limited Compositions de tadalafil
WO2018142189A1 (fr) * 2017-02-02 2018-08-09 Dukebox Sp. Z O. O. Procédé de fabrication d'une suspension de nanoparticules de tadalafil ou de citrate de sildénafil
CN109528675A (zh) * 2018-12-31 2019-03-29 杭州康本医药科技有限公司 一种他达拉非肠溶片剂及其制备方法

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