WO2022060309A1 - Long-term stable anagrelid capsule composition - Google Patents

Long-term stable anagrelid capsule composition Download PDF

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Publication number
WO2022060309A1
WO2022060309A1 PCT/TR2020/050858 TR2020050858W WO2022060309A1 WO 2022060309 A1 WO2022060309 A1 WO 2022060309A1 TR 2020050858 W TR2020050858 W TR 2020050858W WO 2022060309 A1 WO2022060309 A1 WO 2022060309A1
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Prior art keywords
anagrelide
lactose
pharmaceutical composition
capsule
composition according
Prior art date
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PCT/TR2020/050858
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French (fr)
Inventor
Hatice Öncel
Onur PINARBAŞLI
Feriştah BILGIN
Bahar KÖKSEL ÖZGEN
Asuman AYBEY DOĞANAY
Nagehan SARRAÇOĞLU
Original Assignee
İlko İlaç Sanayi̇ Ve Ti̇caret A.Ş.
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Publication date
Application filed by İlko İlaç Sanayi̇ Ve Ti̇caret A.Ş. filed Critical İlko İlaç Sanayi̇ Ve Ti̇caret A.Ş.
Priority to PCT/TR2020/050858 priority Critical patent/WO2022060309A1/en
Priority to EP20954278.6A priority patent/EP4213815A4/en
Publication of WO2022060309A1 publication Critical patent/WO2022060309A1/en

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    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the present invention relates to formulate pharmaceutical capsule composition comprising anagrelide hydrochloride, a process for the manufacture of said formulation with long-term storage stable properties.
  • Anagrelide (Imidazo (2,1 -b) quinazolin-2 (3H)-one,6,7-dichloro-1 ,5-dihydromono hydrochloride) is a pharmaceutically active compound useful for the treatment of essential thrombocythaemia (ET). Its molecular formula is C10H7CI2N3O and it is represented by Formula I (shown below);
  • Anagrelide was first disclosed in US 3932407 as a compound useful at blood platelet anti-aggregative and/or antihypertensive and/or bronchodilator agents in mammals, including humans. In 1997, anagrelide was approved in the United States as a therapeutic agent for thrombocytosis associated with myeloproliferative neoplasm; in 2004, it was approved in Europe for the treatment of high-risk essential thrombocythemia patients.
  • Essential thrombocythaemia which is the most often occurring myeloproliferative disorder is a clonal malignant disorder arising from stem cell. It is a myeloproliferative neoplasm (MPN), which is, characterized by a sustained platelet increase in the peripheral blood and anomalous megakaryocyte growth in bone marrow biopsy.
  • Treatment goals comprise prevention of thrombohemorrhagic events (THEs), progression to myelofibrosis (MF) or acute leukemia (AL), and the onset of secondary malignancies.
  • TEEs thrombohemorrhagic events
  • MF myelofibrosis
  • AL acute leukemia
  • Anagrelide anagrelide hydrochloride
  • is an imidazoquinazoline derivative which lowers platelet count probably by inhibiting thrombopoiesis and reduces platelet aggregation.
  • Anagrelid is marketed with names Thromboreductin® and Xagrid® (or Agrylin®) and these are oral imidazoquinazolines registered as orphan drugs in Europe.
  • Xagrid® (or Agrylin®) is an immediate release capsule which releases more than 90% of its active in vitro within the first 10 minutes. It is medicinal product indicated for the reduction of elevated platelet counts in at risk ET patients who are intolerant to their current therapy or whose elevated platelet counts are not reduced to an acceptable level by their current therapy.
  • Xagrid® is in the form of hard gelatin capsules, each of which contains anagrelide hydrochloride equivalent to 0.5 mg of anagrelide.
  • Agrylin® (Shire US Inc.) is used for reference product.
  • EP1351668B1 and EP1351668B1 disclose pharmaceutical compositions with sustained release dissolution profiles.
  • EP2367539B1 (AOP Orphan Pharmaceutical) relates to a novel pharmaceutical composition comprising anagrelide hydrochloride in combination with lactose monohydrate and its use for the treatment of essential thrombocythemia. It is related to non-immediate and highly consistent release pharmaceutical composition.
  • EP2549983 B1 (AOP Orphan Pharmaceutical) relates to a novel pharmaceutical composition comprising anagrelide hydrochloride in combination with a non-pH dependent polymer and a pharmaceutically acceptable watersoluble acid and its use for the treatment of essential thrombocythemia.
  • EP2915526A1 discloses a pharmaceutical composition of anagrelide hydrochloride monohydrate having a low content of total impurities originating from the decomposition of anagrelide hydrochloride monohydrate.
  • prepared capsules were subjected to stability tests at time 0 and 1 month or 53 days at 25°C/ 60% relative humidity (RH), 30°C/ 65% RH, 30°C/ 75% RH and 40°C/ 75% RH.
  • the problem for the anagrelide capsule composition is the high use of lactose.
  • the reference products, Xagrid® (Agrylin®) capsule comprises a combination of 53.7 mg lactose monohydrate and 65.8 mg anhydrous lactose and Thromboreductin® comprises 93.9 mg lactose monohydrate.
  • Lactase is a disacharidase (P-galactosidase) expressed on the tips of the villi of the small intestine having the ability to hydrolyze lactose into galactose and glucose.
  • lactasephlorizin hydrolase (LPH) activity is responsible for lactose intolerance/malabsorption leading to diarrhea, abdominal pain or bloating after lactose ingestion.
  • LPH lactasephlorizin hydrolase
  • Typical treatments for lactose intolerance is by decreasing the amount of lactose in the diet, taking lactose supplements, or treating the underlying disease.
  • It is an object of the present invention to provide a stable pharmaceutical composition comprising therapeutically effective amount of anagrelide or a pharmaceutically acceptable salt thereof having immediate release properties and low amount of lactose content.
  • the present invention provides a stable immediate release Anagrelide 0.5 mg capsule composition having low content of total impurities originating from the decomposition of anagrelide hydrochloride.
  • a long-term stable oral pharmaceutical capsule composition comprises anagrelide or a pharmaceutically acceptable salt thereof as active ingredient, lactose monohydrate, lactose anhydrous and at least one other pharmaceutically acceptable excipient, wherein the weight ratio of lactose monohydrate to lactose anhydrous is about 2.5:1 .
  • a long-term stable oral pharmaceutical capsule composition comprises anagrelide or a pharmaceutically acceptable salt thereof as active ingredient, lactose monohydrate, lactose anhydrous and at least one filler/diluent, disintegrant, binder and lubricant, wherein the weight ratio of lactose monohydrate to lactose anhydrous is about 2.5:1 .
  • the active ingredient is anagrelide hydrochloride.
  • the filler/diluent is a combination of lactose and microcrystalline cellulose.
  • the disintegrant is crospovidone.
  • the binder is povidone.
  • the lubricant is magnesium stearate.
  • a long-term stable oral pharmaceutical capsule composition comprises 0.57 mg anagrelide hydrochloride, 50.9 mg lactose monohydrate, 20.5 mg lactose anhydrate, 22.5 mg microcrystalline cellulose, 6.0 mg povidone, 5.5 mg crospovidone and 1.0 mg magnesium stearate, wherein the said composition is prepared by wet granulation process.
  • anagrelide is used for pharmaceutically acceptable salts, hydrates and/or solvates thereof; anagrelide, anagrelide hydrochloride or anagrelide hydrochloride monohydrate are used interchangeably.
  • stable refers to a pharmaceutical composition comprising anagrelide or a pharmaceutically acceptable salt thereof wherein the total content of degradation impurities originating from the decomposition of anagrelide does not exceed 2.0 % area and most preferably 1.5 % area determined as specified in the US Pharmacopoeia official monograph for anagrelide capsules.
  • the term ‘long-term stable’ refers to a pharmaceutical composition comprising anagrelide or a pharmaceutically acceptable salt thereof wherein the total content of degradation impurities originating from the decomposition of anagrelide does not exceed 1 .5 % area determined as specified in the US Pharmacopoeia official monograph for anagrelide capsules for at least about 6 months at 40°C ⁇ 2°C, 75%RH ⁇ 5% and 24 months at 25°C ⁇ 2°C, 60% ⁇ 5% RH conditions.
  • the active substance anagrelide hydrochloride is present in the form of micronized anagrelide having a particle size of D90 less than 10 pm and D50 less than 6 pm. It is important to use a small particle size raw material in order to eliminate the problems that may occur in content uniformity by preparing the capsule composition containing low concentration anagrelide active substance.
  • D10 ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • the wet granulation method was preferred in the preparation of pharmaceutical dosage form.
  • One or more pharmaceutically acceptable excipients used according to the invention includes without any limitations, those that are conventionally used, for the capsule dosage form e.g. fillers, diluents, disintegrants, binders and lubricants. Suitably, also other excipients that are appropriate for the chosen dosage form may be present. These excipients include but are not limited to coatings, colors, flavors, glidants, retardants, spheronisation aids etc. Some excipients present in the formulation according to the invention may have multiple functions.
  • fillers fill out the size of a composition, making it practical to produce and convenient for the consumer to use.
  • suitable filler/diluent include but are not limited to lactose, microcrystalline cellulose, mannitol, ethyl cellulose, sorbitol, starch, sucrose, calcium phosphate, powdered cellulose, silicified microcrystalline cellulose, isomalt, and mixtures thereof.
  • lactose is widely used in pharmaceutical formulations as a diluent and filler-binder in oral capsule and tablet formulations.
  • lactose as used herein comprises lactose monohydrate and/or lactose anhydrous.
  • lactose monohydrate and lactose anhydrous are used together.
  • Anhydrous lactose can be used with moisture-sensitive drugs due to its low moisture content.
  • lactose anhydrous is incompatible with strong oxidizers.
  • mixtures containing a hydrophobic leukotriene antagonist and anhydrous lactose or lactose monohydrate were stored for six weeks at 40°C and 75% RH, the mixture containing anhydrous lactose showed greater moisture uptake and drug degradation (Handbook of Pharmaceutical Excipients, 6 th Edition, Lactose Anhydrous, page 359-361). This is the reason for using lactose in a mixture of lactose monohydrate and lactose anhydrous instead of using only lactose anhydrous.
  • lactose intolerance which occurs in individuals with a deficiency of the intestinal enzyme lactase, and is associated with oral ingestion of amounts well over those found in solid dosage forms. This is also critical for patients who have lactose intolerance. This is the reason for using lactose in minimum content.
  • a disintegrant is a substance which helps the composition break up once ingested.
  • suitable disintegrants include, but are not limited to one or more of starches, celluloses, algins, and cross-linked polymers.
  • a group of disintegrants referred to as “super-disintegrants” are generally used at a low level in the solid dosage form, typically 1 to 10% by weight relative to the total weight of the dosage unit.
  • super-disintegrants are croscarmelose, crospovidone and sodium starch glycolate, which represent examples of cross-linked cellulose, cross-linked polymer and cross-linked starch, respectively. In this present invention, crospovidone is used as a disintegrant.
  • Suitable binders include, but are not limited to one or more of povidone, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxymethyl cellulosexylitol, starch, and the like.
  • povidone is used as a binder.
  • povidone is used in a variety of pharmaceutical formulations, it is primarily used in solid-dosage forms. In the present invention, povidone is used in an amount of 1% to 7% based on total weight of the formulation.
  • the pharmaceutical composition comprises magnesium stearate as a lubricant.
  • Magnesium stearate is primarily used as a lubricant in capsule and tablet manufacture at concentrations between 0.25% and 5.0% w/w.
  • the amount of magnesium stearate ranges from 0.8 to 1 .2% by weight in respect to the total amount of the pharmaceutical composition preferably ranges from 0.9 to 1.1% by weight in respect to the total amount of the pharmaceutical composition.
  • magnesium stearate which is also included in the original content, was used to provide the desired powder flow from the final powder mixture. All ingredients used in Anagrelid 0.5 mg capsule production are standard excipients used in capsule formulations and all excipients are included in the European Pharmacopoeia monographs and comply with the relevant specifications.
  • compositions of this invention are detailed below showing examples. However, pharmaceutical compounds of this invention are not restricted to the following examples.
  • the granules of the composition are prepared by wet granulation with following formulation given at Table 1 .
  • the preparation process of the granules is described as: a.
  • the active agent, anagrelid hydrochloride, and at least one pharmaceutically acceptable excipient were weighed and mixed.
  • b. The components of step (a) were added to a high shear mixer and granulated with water.
  • c. The granules obtained from step (b) were dried in a fluidized bed dryer.
  • the dried granules obtained from step (c) were grinded.
  • At least one extra-granular pharmaceutically acceptable excipient was mixed with the dried granules obtained in step (d).
  • a pharmaceutically acceptable lubricant is mixed with the granules obtained from step (e) before being encapsulated in hard capsules. Table 1.
  • Comparative dissolution tests were conducted based on the general dissolution test method. The analysis was performed according to FDA Dissolution Methods - Anagrelide HCI Capsule. The progress of dissolution is monitored for 45 minutes (recommended sampling times: 5, 10, 15, 30 and 45 minutes). Dissolution test was performed at USP Apparatus I (basket), speed 100 rpm, 900 mL volume with 0.1 N HCI (FDA medium), pH 4.5 and pH 6.8 mediums. Dissolution testing measures the portion (%) of Anagrelide that has been released from capsule and has dissolved in the dissolution medium. Dissolved anagrelide content was determined spectrophotometrically by a validated HPLC method at 254 nm.
  • Comparative dissolution tests were conducted with test products (F-01 , F-02, F-03 and F-04) and reference product of Agrylin® 0.5 mg Capsule.
  • the conditional release profiles of the test products and reference product were plotted as the cumulative percent of drug dissolved vs. time.
  • the dissolution profiles were compared; the dissolution profiles obtained were evaluated by similarity factor (£?) (Helmy & Bedaiwy, 2013).
  • An /2 value between 50 and 100 suggests that the two dissolution profiles are similar (EMEA Guideline on the Investigation of Bioequivalence, 2010).
  • test product of F-04 was selected for proceeding studies according to dissolution similarity results with reference product.
  • the pharmaceutical anagrelide capsule composition according to the present invention exhibits a dissolution profile such that about 85% of the anagrelide is released within 15 minutes; and wherein the release rate is measured in USP Apparatus I (basket), speed 100 rpm, 900 mL volume with 0.1 N HCI (FDA medium) at 37°C ⁇ 0.5°C ( Figure I).
  • the stability of a drug substance is an important factor in the manufacture of safe and effective pharmaceutical products. Stability studies are required to be submitted by any applicant seeking approval for a new pharmaceutical product.
  • the rules in force e.g. "Note for Guidance on Impurities in New Drug Products” CPMP/ICH/2738/99, issued by EMEA, European Medicines Agency) provide strict limitations for impurities, nevertheless it is better to prevent or reduce as possible the degradation to avoid the exposure of patients to substances.
  • the stability of a pharmaceutical dosage form is related to maintaining its physical, chemical, microbiological, therapeutic, and toxicological properties when stored, i.e., in a particular container and environment.
  • Accelerated stability tests are performed by storing a product in stress conditions. These tests allow predicting the shelf life of the product over the years when it will be stored in normal storage conditions.
  • the accelerated stability test in this case was performed according to the EMEA Guideline on Stability Testing (CPMP/QWP/ 122/02, rev 1), i.e. by maintaining the product in its container at a temperature of 40°C ⁇ 2°C and 75% ⁇ 5 %RH (Relative Humidity) for six months.
  • the accelerated stability condition is temperature of 40°C ⁇ 2°C and 75 % ⁇ 5°C RH for up to 6 months and ambient stability condition is temperature of 25°C ⁇ 2°C and 60% ⁇ 5% RH for up to 24 months.
  • Test product capsule formulations were packed in Alu-Alu containers and they were charged on to the stability cabinets. Samples were taken out at each stability stage interval and submitted for analysis. The results are summarized in the following Table 3.
  • FDA United States Food and Drug Administration
  • Reference drug means an anagrelide hydrochloride product as described in U.S. Federal Food and Drug Administration's New Drug Application No. 021368 approved on Nov 21 , 2003 as provided in the U.S. Federal Food and Drug Administration's Orange Book, Approved Drug Products with Therapeutic Equivalence Evaluations.
  • the pharmacokinetic parameters were estimated by non-compartmental methods using actual elapsed time from dosing; maximum observed plasma concentration (C m ax), area under the plasma concentration versus time curve from time zero until infinity (AUCo-int), area under the plasma concentration versus time curve from time zero until time of last quantifiable concentration (AUCo-t).
  • Anagrelide 0.5 mg capsule composition of present invention (Test product - F04; Anagrelide 0.5 mg capsule Batch No: 1910819001 ) against Agrylin® (Anagrelid HCI) Capsule, Shire US Inc. - USA (Batch No: AF9326E) as using an open-label, single dose, 2-period crossover, randomized design under fasting conditions.

Abstract

The invention relates to develop a long-term stable immediate release Anagrelide 0.5 mg capsule composition having low content of total impurities originating from the decomposition of anagrelide hydrochloride and low amount of lactose content.

Description

LONG-TERM STABLE ANAGRELID CAPSULE COMPOSITION
Technical field:
The present invention relates to formulate pharmaceutical capsule composition comprising anagrelide hydrochloride, a process for the manufacture of said formulation with long-term storage stable properties.
Prior Art:
Anagrelide (Imidazo (2,1 -b) quinazolin-2 (3H)-one,6,7-dichloro-1 ,5-dihydromono hydrochloride) is a pharmaceutically active compound useful for the treatment of essential thrombocythaemia (ET). Its molecular formula is C10H7CI2N3O and it is represented by Formula I (shown below);
Figure imgf000002_0001
Formula (I)
Anagrelide was first disclosed in US 3932407 as a compound useful at blood platelet anti-aggregative and/or antihypertensive and/or bronchodilator agents in mammals, including humans. In 1997, anagrelide was approved in the United States as a therapeutic agent for thrombocytosis associated with myeloproliferative neoplasm; in 2004, it was approved in Europe for the treatment of high-risk essential thrombocythemia patients.
Essential thrombocythaemia which is the most often occurring myeloproliferative disorder is a clonal malignant disorder arising from stem cell. It is a myeloproliferative neoplasm (MPN), which is, characterized by a sustained platelet increase in the peripheral blood and anomalous megakaryocyte growth in bone marrow biopsy. Treatment goals comprise prevention of thrombohemorrhagic events (THEs), progression to myelofibrosis (MF) or acute leukemia (AL), and the onset of secondary malignancies. Anagrelide (anagrelide hydrochloride) is an imidazoquinazoline derivative which lowers platelet count probably by inhibiting thrombopoiesis and reduces platelet aggregation.
Anagrelid is marketed with names Thromboreductin® and Xagrid® (or Agrylin®) and these are oral imidazoquinazolines registered as orphan drugs in Europe. Xagrid® (or Agrylin®) is an immediate release capsule which releases more than 90% of its active in vitro within the first 10 minutes. It is medicinal product indicated for the reduction of elevated platelet counts in at risk ET patients who are intolerant to their current therapy or whose elevated platelet counts are not reduced to an acceptable level by their current therapy. Xagrid® is in the form of hard gelatin capsules, each of which contains anagrelide hydrochloride equivalent to 0.5 mg of anagrelide. In this invention, Agrylin® (Shire US Inc.) is used for reference product.
EP1351668B1 and EP1351668B1 disclose pharmaceutical compositions with sustained release dissolution profiles.
EP2367539B1 (AOP Orphan Pharmaceutical) relates to a novel pharmaceutical composition comprising anagrelide hydrochloride in combination with lactose monohydrate and its use for the treatment of essential thrombocythemia. It is related to non-immediate and highly consistent release pharmaceutical composition.
EP2549983 B1 (AOP Orphan Pharmaceutical) relates to a novel pharmaceutical composition comprising anagrelide hydrochloride in combination with a non-pH dependent polymer and a pharmaceutically acceptable watersoluble acid and its use for the treatment of essential thrombocythemia.
In the literature, there are some studies specially stability studies related to degradation of anagrelide into impurity B which is chemically known as [2-amino-5,6- dichloroquinazoline-3(4H)-yl] acetic acid. EP2915526A1 discloses a pharmaceutical composition of anagrelide hydrochloride monohydrate having a low content of total impurities originating from the decomposition of anagrelide hydrochloride monohydrate. In this study, prepared capsules were subjected to stability tests at time 0 and 1 month or 53 days at 25°C/ 60% relative humidity (RH), 30°C/ 65% RH, 30°C/ 75% RH and 40°C/ 75% RH.
In addition to degradation, there is another concern about the patients who have lactose intolerance. The problem for the anagrelide capsule composition is the high use of lactose. The reference products, Xagrid® (Agrylin®) capsule comprises a combination of 53.7 mg lactose monohydrate and 65.8 mg anhydrous lactose and Thromboreductin® comprises 93.9 mg lactose monohydrate. Lactase is a disacharidase (P-galactosidase) expressed on the tips of the villi of the small intestine having the ability to hydrolyze lactose into galactose and glucose. Inadequate lactasephlorizin hydrolase (LPH) activity is responsible for lactose intolerance/malabsorption leading to diarrhea, abdominal pain or bloating after lactose ingestion. Approximately 70% of the world's population has primary lactase deficiency. Typical treatments for lactose intolerance is by decreasing the amount of lactose in the diet, taking lactose supplements, or treating the underlying disease.
These are the reasons for the need to develop a long-term stable anagrelide capsule formulation comprising low amount of lactose content.
Description of the Invention:
It is an object of the present invention to provide a stable pharmaceutical composition comprising therapeutically effective amount of anagrelide or a pharmaceutically acceptable salt thereof having immediate release properties and low amount of lactose content.
The present invention provides a stable immediate release Anagrelide 0.5 mg capsule composition having low content of total impurities originating from the decomposition of anagrelide hydrochloride.
In the first aspect, there is a need for preventing the formation of degradation products from anagrelide or, at least, to maintain an acceptable, low concentration of such degradation products throughout the long term shelf-life.
In the second aspect, people with lactose intolerance need a bioequivalent product that contains low lactose but will exhibit the same effects of the reference product, Agrylin® Capsule.
According to the invention, a long-term stable oral pharmaceutical capsule composition comprises anagrelide or a pharmaceutically acceptable salt thereof as active ingredient, lactose monohydrate, lactose anhydrous and at least one other pharmaceutically acceptable excipient, wherein the weight ratio of lactose monohydrate to lactose anhydrous is about 2.5:1 . In a preferred embodiment, a long-term stable oral pharmaceutical capsule composition comprises anagrelide or a pharmaceutically acceptable salt thereof as active ingredient, lactose monohydrate, lactose anhydrous and at least one filler/diluent, disintegrant, binder and lubricant, wherein the weight ratio of lactose monohydrate to lactose anhydrous is about 2.5:1 .
In a preferred embodiment, the active ingredient is anagrelide hydrochloride.
In a preferred embodiment, the filler/diluent is a combination of lactose and microcrystalline cellulose.
In a preferred embodiment, the disintegrant is crospovidone.
In a preferred embodiment, the binder is povidone.
In a preferred embodiment, the lubricant is magnesium stearate.
In a more preferred embodiment, a long-term stable oral pharmaceutical capsule composition comprises 0.57 mg anagrelide hydrochloride, 50.9 mg lactose monohydrate, 20.5 mg lactose anhydrate, 22.5 mg microcrystalline cellulose, 6.0 mg povidone, 5.5 mg crospovidone and 1.0 mg magnesium stearate, wherein the said composition is prepared by wet granulation process.
In the present invention, the term ‘anagrelide’ is used for pharmaceutically acceptable salts, hydrates and/or solvates thereof; anagrelide, anagrelide hydrochloride or anagrelide hydrochloride monohydrate are used interchangeably.
As used herein, the term "stable" refers to a pharmaceutical composition comprising anagrelide or a pharmaceutically acceptable salt thereof wherein the total content of degradation impurities originating from the decomposition of anagrelide does not exceed 2.0 % area and most preferably 1.5 % area determined as specified in the US Pharmacopoeia official monograph for anagrelide capsules. More preferably, the term ‘long-term stable’ refers to a pharmaceutical composition comprising anagrelide or a pharmaceutically acceptable salt thereof wherein the total content of degradation impurities originating from the decomposition of anagrelide does not exceed 1 .5 % area determined as specified in the US Pharmacopoeia official monograph for anagrelide capsules for at least about 6 months at 40°C±2°C, 75%RH±5% and 24 months at 25°C±2°C, 60% ± 5% RH conditions. In the present invention, the active substance anagrelide hydrochloride is present in the form of micronized anagrelide having a particle size of D90 less than 10 pm and D50 less than 6 pm. It is important to use a small particle size raw material in order to eliminate the problems that may occur in content uniformity by preparing the capsule composition containing low concentration anagrelide active substance.
A common approach to define the distribution width is to cite three values on the x-axis as D10, D50 and D90. The D50, named as median, has been defined as the diameter where 50 percent of the distribution lies below this value. Similarly, D90 has been defined as 90 percent of the distribution lies below, and 10 percent of the population lies below the D10.
Since the anagrelid HCI active substance is in low dosage in the product content and the desired solubility and homogeneity cannot be achieved in the powder mixture to be prepared by the direct mixing method, the wet granulation method was preferred in the preparation of pharmaceutical dosage form.
One or more pharmaceutically acceptable excipients used according to the invention includes without any limitations, those that are conventionally used, for the capsule dosage form e.g. fillers, diluents, disintegrants, binders and lubricants. Suitably, also other excipients that are appropriate for the chosen dosage form may be present. These excipients include but are not limited to coatings, colors, flavors, glidants, retardants, spheronisation aids etc. Some excipients present in the formulation according to the invention may have multiple functions.
The term 'filler' and the term 'diluent' are herein used interchangeably. Fillers fill out the size of a composition, making it practical to produce and convenient for the consumer to use. Examples of suitable filler/diluent include but are not limited to lactose, microcrystalline cellulose, mannitol, ethyl cellulose, sorbitol, starch, sucrose, calcium phosphate, powdered cellulose, silicified microcrystalline cellulose, isomalt, and mixtures thereof. In the present invention, a combination of lactose and microcrystalline cellulose are used. Lactose is widely used in pharmaceutical formulations as a diluent and filler-binder in oral capsule and tablet formulations. For the purposes of the invention, lactose as used herein comprises lactose monohydrate and/or lactose anhydrous. In this present invention, lactose monohydrate and lactose anhydrous are used together. Anhydrous lactose can be used with moisture-sensitive drugs due to its low moisture content. However, lactose anhydrous is incompatible with strong oxidizers. When mixtures containing a hydrophobic leukotriene antagonist and anhydrous lactose or lactose monohydrate were stored for six weeks at 40°C and 75% RH, the mixture containing anhydrous lactose showed greater moisture uptake and drug degradation (Handbook of Pharmaceutical Excipients, 6th Edition, Lactose Anhydrous, page 359-361). This is the reason for using lactose in a mixture of lactose monohydrate and lactose anhydrous instead of using only lactose anhydrous.
On the other hand, adverse reactions to lactose are largely due to lactose intolerance, which occurs in individuals with a deficiency of the intestinal enzyme lactase, and is associated with oral ingestion of amounts well over those found in solid dosage forms. This is also critical for patients who have lactose intolerance. This is the reason for using lactose in minimum content.
A disintegrant is a substance which helps the composition break up once ingested. Examples of suitable disintegrants include, but are not limited to one or more of starches, celluloses, algins, and cross-linked polymers. A group of disintegrants referred to as “super-disintegrants” are generally used at a low level in the solid dosage form, typically 1 to 10% by weight relative to the total weight of the dosage unit. Examples of super-disintegrants are croscarmelose, crospovidone and sodium starch glycolate, which represent examples of cross-linked cellulose, cross-linked polymer and cross-linked starch, respectively. In this present invention, crospovidone is used as a disintegrant.
Examples of suitable binders include, but are not limited to one or more of povidone, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxymethyl cellulosexylitol, starch, and the like. In this present invention, povidone is used as a binder. Although povidone is used in a variety of pharmaceutical formulations, it is primarily used in solid-dosage forms. In the present invention, povidone is used in an amount of 1% to 7% based on total weight of the formulation.
Examples of suitable lubricants include, but are not limited to one or more of magnesium stearate and stearic acid. In the present invention, the pharmaceutical composition comprises magnesium stearate as a lubricant. Magnesium stearate is primarily used as a lubricant in capsule and tablet manufacture at concentrations between 0.25% and 5.0% w/w. In this invention, the amount of magnesium stearate ranges from 0.8 to 1 .2% by weight in respect to the total amount of the pharmaceutical composition preferably ranges from 0.9 to 1.1% by weight in respect to the total amount of the pharmaceutical composition.
During the capsule filling process, magnesium stearate, which is also included in the original content, was used to provide the desired powder flow from the final powder mixture. All ingredients used in Anagrelid 0.5 mg capsule production are standard excipients used in capsule formulations and all excipients are included in the European Pharmacopoeia monographs and comply with the relevant specifications.
Compositions of this invention are detailed below showing examples. However, pharmaceutical compounds of this invention are not restricted to the following examples.
Example 1. Formulation and preparation method of Anagrelid 0.5 mg Capsule
The granules of the composition are prepared by wet granulation with following formulation given at Table 1 . The preparation process of the granules is described as: a. The active agent, anagrelid hydrochloride, and at least one pharmaceutically acceptable excipient were weighed and mixed. b. The components of step (a) were added to a high shear mixer and granulated with water. c. The granules obtained from step (b) were dried in a fluidized bed dryer. d. The dried granules obtained from step (c) were grinded. e. At least one extra-granular pharmaceutically acceptable excipient was mixed with the dried granules obtained in step (d). f. Finally a pharmaceutically acceptable lubricant is mixed with the granules obtained from step (e) before being encapsulated in hard capsules. Table 1. Unit formula of pharmaceutical capsule compositions
Figure imgf000009_0001
Example 2. Comparative Dissolution Profiles:
Comparative dissolution tests were conducted based on the general dissolution test method. The analysis was performed according to FDA Dissolution Methods - Anagrelide HCI Capsule. The progress of dissolution is monitored for 45 minutes (recommended sampling times: 5, 10, 15, 30 and 45 minutes). Dissolution test was performed at USP Apparatus I (basket), speed 100 rpm, 900 mL volume with 0.1 N HCI (FDA medium), pH 4.5 and pH 6.8 mediums. Dissolution testing measures the portion (%) of Anagrelide that has been released from capsule and has dissolved in the dissolution medium. Dissolved anagrelide content was determined spectrophotometrically by a validated HPLC method at 254 nm.
Comparative dissolution tests were conducted with test products (F-01 , F-02, F-03 and F-04) and reference product of Agrylin® 0.5 mg Capsule. The conditional release profiles of the test products and reference product were plotted as the cumulative percent of drug dissolved vs. time. The dissolution profiles were compared; the dissolution profiles obtained were evaluated by similarity factor (£?) (Helmy & Bedaiwy, 2013). An /2 value between 50 and 100 suggests that the two dissolution profiles are similar (EMEA Guideline on the Investigation of Bioequivalence, 2010). The similarity factor (£?) values of test products (F-01 , F-02, F-03, F-04) and reference product (R - Agrylin® 0.5 mg Capsule) for the different pH media are given at Table 2. Table 2. Similarity factor (£?) values of test products (F-01 , F-02, F-03, F-04) and reference product (R - Agrylin® 0.5 mg Capsule) for the different pH media (n=12)
Figure imgf000010_0001
According to 2 results, test product of F-04 was selected for proceeding studies according to dissolution similarity results with reference product.
The pharmaceutical anagrelide capsule composition according to the present invention (F-04) exhibits a dissolution profile such that about 85% of the anagrelide is released within 15 minutes; and wherein the release rate is measured in USP Apparatus I (basket), speed 100 rpm, 900 mL volume with 0.1 N HCI (FDA medium) at 37°C ±0.5°C (Figure I).
Example 3. Stability Studies
The stability of a drug substance is an important factor in the manufacture of safe and effective pharmaceutical products. Stability studies are required to be submitted by any applicant seeking approval for a new pharmaceutical product. The rules in force (e.g. "Note for Guidance on Impurities in New Drug Products" CPMP/ICH/2738/99, issued by EMEA, European Medicines Agency) provide strict limitations for impurities, nevertheless it is better to prevent or reduce as possible the degradation to avoid the exposure of patients to substances.
The stability of a pharmaceutical dosage form is related to maintaining its physical, chemical, microbiological, therapeutic, and toxicological properties when stored, i.e., in a particular container and environment.
It is known that many drugs exhibit poor or modest shelf stability. The presence of degradation products of these drugs can give rise to efficacy or toxicity issues, but even if they do not, the diminution of the concentration of a drug as a result of its degradation is inherently undesirable, as it make therapy with the drug less certain. Stability issues can be caused by environmental factors such as humidity, temperature and the like. However, degradation may result from, or be accelerated by, interactions of drug substances with pharmaceutical excipients such as fillers, binders, lubricants, glidants and disintegrating agents or impurities contained in any of these excipients.
Accelerated stability tests are performed by storing a product in stress conditions. These tests allow predicting the shelf life of the product over the years when it will be stored in normal storage conditions. The accelerated stability test in this case was performed according to the EMEA Guideline on Stability Testing (CPMP/QWP/ 122/02, rev 1), i.e. by maintaining the product in its container at a temperature of 40°C ± 2°C and 75% ± 5 %RH (Relative Humidity) for six months.
Thus, in the development of capsule form, the applicant carried out both accelerated and ambient stability studies for the test and reference products. The accelerated stability condition is temperature of 40°C ± 2°C and 75 % ± 5°C RH for up to 6 months and ambient stability condition is temperature of 25°C±2°C and 60% ± 5% RH for up to 24 months.
Test product capsule formulations were packed in Alu-Alu containers and they were charged on to the stability cabinets. Samples were taken out at each stability stage interval and submitted for analysis. The results are summarized in the following Table 3.
Table 3. Comparative stability results (degradation products) for Test products initially and after 6 months at 40°C±2°C/ 75%±5 %RH and after 24 months at 25°C±2°C/ 60±5% Relative Humidity, RH±5% storage conditions.
Degradation Product (%)
After 6 months After 24 months Initially (40°C±2°C, (25°C±2°C,
75%RH) 60%RH)
. r. Total . „ Total . „ Total
Imp. B . .. Imp. B . .. Imp. B . Impurity Impurity Impurity
Test
Product 0.17 0.23 0.47 0.63 0.50 0.66
F-04
Reference product 0.46 0.59 0.83 0.97 0.92 1.16
(Agrylin®)
ND: Not detected. Example 4. Bioequivalence study
The United States Food and Drug Administration (FDA) defines bioequivalence as ‘the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study' (US FDA Code of Federal Regulations, 2019).
"Reference drug" means an anagrelide hydrochloride product as described in U.S. Federal Food and Drug Administration's New Drug Application No. 021368 approved on Nov 21 , 2003 as provided in the U.S. Federal Food and Drug Administration's Orange Book, Approved Drug Products with Therapeutic Equivalence Evaluations.
The pharmacokinetic parameters were estimated by non-compartmental methods using actual elapsed time from dosing; maximum observed plasma concentration (Cmax), area under the plasma concentration versus time curve from time zero until infinity (AUCo-int), area under the plasma concentration versus time curve from time zero until time of last quantifiable concentration (AUCo-t).
The in-vivo studies were conducted in 42 healthy volunteers to assess the bioequivalence of the Anagrelide 0.5 mg capsule composition of present invention (Test product - F04; Anagrelide 0.5 mg capsule Batch No: 1910819001 ) against Agrylin® (Anagrelid HCI) Capsule, Shire US Inc. - USA (Batch No: AF9326E) as using an open-label, single dose, 2-period crossover, randomized design under fasting conditions.
Evaluation of the pharmacokinetic profiles and the relative bioavailability of anagrelide from the Test product - F04 (T) in comparison with the reference product - Agrylin® (R) so that to demonstrate the bioequivalence of the test preparation with the reference preparation administered under fasting conditions.
The parameters AUCo-t, AUCo-int, Cmax, tmax and t% of anagrelide were determined with the program Phoenix WinNonlin V8.1.0.3530. Pharmacokinetic parameters of primary target variables AUCo-t and Cmax of anagrelide as well as of secondary variable AUCo-int were tested with respect to fasting conditions for statistically significant differences by means of the ANOVA test procedure following In-transformation of data and 90 % confidence intervals (two one-sided t-tests) were calculated. Differences in the parameter tmax were statistically tested by nonparametric analysis (90 % confidence intervals; two one-sided Wilcoxon tests). The results are given at the following tables (Table 4): Table 4. Statistical Results of anagrelide at fasting condition for composition of Test product - F04 against Reference product (Agrylin® Capsule).
Statistical Results of Anagrelide (Test vs reference); n=42, fasting condition
Primary pharmacokinetic parameters:
90% confidence interval of AUCo-t ANOVA (two one-sided t-tests): 94.09% - 104.75% point estimator (ratio): 99.28%
90% confidence interval of
Cmax ANOVA (two one-sided t-tests): 85.62% - 104.03% point estimator (ratio): 94.37%
Secondary pharmacokinetic parameters:
90% confidence interval of
AUCo- ANOVA (two one-sided t-tests): 94.50% - 105.10% point estimator (ratio): 99.66%
Based on the results of Table 4, the 90 % confidence intervals for the T/R ratios of Intransformed AUCo-t and In-transformed Cmax of anagrelide meet the bioequivalence criteria of 80.00 % - 125.00 %. Also for the secondary pharmacokinetic target variable
AUCo-inf Of anagrelide the 90% confidence interval of In-transformed data is included in the bioequivalence acceptance range. The safety profile of both study preparations is well acceptable.
To conclude, bioequivalence between Anagrelide 0.5 mg Capsule (Test Product - F04) and Agrylin® (Anagrelide HCI) Capsule has been demonstrated with 42 healthy male
Caucasian subjects after administration of single oral doses of 0.5 mg anagrelide (as anagrelide HCI) each under fasting conditions.

Claims

1. A long-term stable oral pharmaceutical capsule composition comprising anagrelide or a pharmaceutically acceptable salt thereof as active ingredient, lactose monohydrate, lactose anhydrous and at least one other pharmaceutically acceptable excipient, wherein the weight ratio of lactose monohydrate to lactose anhydrous is about 2.5:1 .
2. The pharmaceutical composition according to claim 1 , wherein said composition comprises at least one filler/diluent, disintegrant, binder and lubricant.
3. The pharmaceutical composition according to claim 2, wherein the filler/diluent is a combination of lactose and microcrystalline cellulose.
4. The pharmaceutical composition according to claim 2, wherein the disintegrant is crospovidone.
5. The pharmaceutical composition according to claim 2, wherein the binder is povidone.
6. The pharmaceutical composition according to claim 2, wherein the lubricant is magnesium stearate.
7. The pharmaceutical composition according to claim 1 , wherein the active ingredient is anagrelide hydrochloride.
8. The pharmaceutical composition according to claim 1 , wherein said composition comprises i. 0.57 mg anagrelide hydrochloride ii. 50.9 mg lactose monohydrate iii. 20.5 mg lactose anhydrate iv. 22.5 mg microcrystalline cellulose v. 6.0 mg povidone vi. 5.5 mg crospovidone vii. 1 .0 mg magnesium stearate
9. The pharmaceutical composition according to claim 1 , wherein said composition is prepared by wet granulation process.
PCT/TR2020/050858 2020-09-18 2020-09-18 Long-term stable anagrelid capsule composition WO2022060309A1 (en)

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