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WO2018158249A1 - Composition pharmaceutique stable à température ambiante comprenant de l'acide carglumique - Google Patents

Composition pharmaceutique stable à température ambiante comprenant de l'acide carglumique Download PDF

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Publication number
WO2018158249A1
WO2018158249A1 PCT/EP2018/054808 EP2018054808W WO2018158249A1 WO 2018158249 A1 WO2018158249 A1 WO 2018158249A1 EP 2018054808 W EP2018054808 W EP 2018054808W WO 2018158249 A1 WO2018158249 A1 WO 2018158249A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
room temperature
temperature stable
solid pharmaceutical
composition according
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.)
Ceased
Application number
PCT/EP2018/054808
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English (en)
Inventor
Salvatore AGOSTINO GIAMMILLARI
Giuseppe Maccari
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.)
Dipharma SA
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Dipharma SA
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 Dipharma SA filed Critical Dipharma SA
Publication of WO2018158249A1 publication Critical patent/WO2018158249A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • 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
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to highly room temperature stable drug dosage forms comprising a compound susceptible to degradation, notably moisture- induced, and at least one pharmaceutically acceptable excipient.
  • the invention regards the Carbamoyl Phosphate Synthetase 1 (CPS l) activator TVcarbamyl-Zv-glutamic acid or carglumic acid, also known as carbaglu ® .
  • CPS l Carbamoyl Phosphate Synthetase 1
  • Carglumic acid is a drug marketed by Orphan Europe SARL under the brand name Carbaglu ® and it is used to treat hyperammonaemia due to N- acetylglutamate synthase primary deficiency, isovaleric acidaemia, methymalonic acidaemia, and propionic acidaemia. It has been approved in Europe in January 2003 for the treatment of N-acetylglutamate synthetase (NAGS) deficiency and in June 2011 for the organic acidaemia. It has also been approved in US by FDA for the treatment of the sole NAGS deficiency.
  • NAGS N-acetylglutamate synthetase
  • CPS 1 is the enzyme catalyzing the first step in ureagenesis. Lack of NAG renders activation of CPS 1, the first enzyme involved in the urea cycle, impossible, and consequently leads to accumulation of a waste product of protein metabolism, the highly toxic ammonia.
  • urea cycle involves a series of biochemical steps in which ammonia is finally converted to urea, this less toxic urea being then removed from the blood through the kidneys and the bladder as urine.
  • secondary deficiency of NAGS also leads to the so-called organic acidemia, or organic aciduria.
  • Isovaleric aciduria, propionic aciduria and methylmalonic aciduria are inherited organic acidurias (OAs) in which impaired organic acid metabolism induces hyperammonaemia (Valayannopoulos V., et al., Orphanet Journal of ' Rare Diseases, 2016, ⁇ 32).
  • Carglumic acid is known for its poor wettability properties, and consequently presence of a wetting agent in the formulation has so far been retained mandatory to confer to the tablets adequate physico-chemical properties.
  • Carbaglu® tablets It is also well known, that one other problem of the actual drug formulation (i.e., Carbaglu® tablets) is its chemical stability. Indeed, Carbaglu® has to be stored in a refrigerator at a temperature ranging from 2°C to 8°C and after the first opening, the in-use stability is a single period of 1 month at a temperature not above 25°C, after which it must be discarded. It will be evident that such storage conditions have an impact in the distribution chain of the medicine, in terms of costs and also in terms of logistics for the patient.
  • EP2777696 claims an improved formulation for preparing a pharmaceutical composition of a high dosage of carglumic acid by direct compression or dry granulation. Said manufacturing process is alleged to confer to the formulation a higher stability as well as a more rapid disintegration of the tablets upon contact with water.
  • direct compression tableting can overcome some of the drawbacks of the wet granulation processes, said direct compression can be however challenging. Indeed, finding the appropriate excipient composition, both qualitatively and quantitatively may result highly difficult, above all when the tablet is a high dosage form.
  • the present invention relates to a highly and durably stable pharmaceutical composition
  • a highly and durably stable pharmaceutical composition comprising crystalline A1 ⁇ 2arbamyl-Zv- glutamic acid, a filler, a disintegrant, a glidant, a lubricant, and optionally a wetting agent and/or a binder.
  • the pharmaceutical composition is for treating patients suffering from urea cycle disorders.
  • the pharmaceutical composition of the present invention is administered in a "therapeutically effective amount".
  • the amount of the pharmaceutical formulation actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, any other potential drug the patient is currently taking, the age, the sex, body weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • an effective dose will be from 10 mg/kg, up to 250 mg/kg if necessary, preferably 10 mg/kg/day to 150 mg/kg/day.
  • the daily dose is preferably given in two equal doses, or even more preferably up to four equal doses.
  • Suitable disintegrant can be chosen from the list comprising sodium croscarmellose, crospovidone, sodium starch glycolate, primellose®, and crosslinked alginic acid.
  • % w/w refers to the percentage of a substance present in the pharmaceutical formulation on a weight by weight basis (i.e., lg/lOOg is equivalent to 1% w/w).
  • highly stable and/or “durably stable” mean that the chemical integrity of the active ingredient is of at least 95% after one month of storage of the drug dosage form at 25°C and 60% RH.
  • room temperature stable means that after three months of storage of the drug dosage form at 25°C and 60% RH, or at 40°C and 75% RH, there is no more than 0.05% of any impurity detected by HPLC.
  • drug dosage form drug dosage form
  • pharmaceutical composition pharmaceutical composition
  • pharmaceutical formulation drug dosage form
  • acid crystals have a PSD (D90) between 130 to 240 ⁇ .
  • said chemical integrity is of at least 96% after one month of storage of the drug dosage form at 25°C and 60% RH.
  • said chemical integrity is of at least 97% after one month of storage of the drug dosage form at 25°C and 60% RH.
  • said chemical integrity is of at least 98% after one month of storage of the drug dosage form at 25°C and 60% RH.
  • said chemical integrity is of at least 99% after one month of storage of the drug dosage form at 25°C and 60% RH.
  • Another embodiment of the invention contemplates chemical integrity of the drug dosage form after three months of storage at 25°C and 60% RH.
  • the chemical integrity of the drug dosage form is of at least 95% after three months of storage of the drug dosage form at 25°C and 60% RH. In a preferred embodiment, the chemical integrity of the drug dosage form is of at least 96% after three months of storage of the drug dosage form at 25°C and 60% RH.
  • the chemical integrity of the drug dosage form is of at least 97% after three months of storage of the drug dosage form at 25°C and 60% RH.
  • the chemical integrity of the drug dosage form is of at least 98% after three months of storage of the drug dosage form at 25°C and 60% RH.
  • the chemical integrity of the drug dosage form is of at least 99% after three months of storage of the drug dosage form at 25°C and 60% RH.
  • Another embodiment of the invention contemplates chemical integrity of the drug dosage form after one month of storage at 40°C and 75% RH.
  • the chemical integrity of the drug dosage form is of at least 95% after one month of storage of the drug dosage form at 40°C and 75% RH. In a preferred embodiment, the chemical integrity of the drug dosage form is of at least 96% after one month of storage of the drug dosage form at 40°C and 75% RH.
  • the chemical integrity of the drug dosage form is of at least 97% after one month of storage of the drug dosage form at 40°C and 75% RH.
  • the chemical integrity of the drug dosage form is of at least 98% after one month of storage of the drug dosage form at 40°C and 75% RH.
  • the chemical integrity of the drug dosage form is of at least 99% after one month of storage of the drug dosage form at 40°C and 75% RH.
  • Another embodiment of the invention contemplates chemical integrity of the drug dosage form after three months of storage at 40°C and 75% RH.
  • the chemical integrity of the drug dosage form is of at least 95% after three months of storage of the drug dosage form at 40°C and 75% RH. In a preferred embodiment, the chemical integrity of the drug dosage form is of at least 96% after three months of storage of the drug dosage form at 40°C and 75% RH.
  • the chemical integrity of the drug dosage form is of at least 97% after three months of storage of the drug dosage form at 40°C and 75% RH.
  • the chemical integrity of the drug dosage form is of at least 98% after three months of storage of the drug dosage form at 40°C and 75% RH.
  • the chemical integrity of the drug dosage form is of at least 99% after three months of storage of the drug dosage form at 40°C and 75% RH. It is submitted that testing at 40°C and 75% RH for a short time such as three months, is considered indicative of stability at 25°C (i.e., room temperature) for a longer period of time (twelve months).
  • the disintegrant is sodium croscarmellose.
  • a suitable lubricant may be chosen from the list comprising stearic acid, magnesium stearate, hydrogenated castor oil, and sodium stearyl fumarate.
  • such pharmaceutical composition comprises hydrogenated castor oil as lubricant.
  • a suitable filler may be chosen from the list comprising pregelatinized starch, microcrystalline cellulose, anhydrous lactose, lactose monohydrate and mannitol.
  • such pharmaceutical composition comprises lactose as a filler.
  • said lactose is lactose monohydrate.
  • a suitable glidant may be colloidal silicon dioxide.
  • such pharmaceutical composition does not comprise any wetting agent.
  • the filler, disintegrant, glidant and lubricant are present in the final pharmaceutical composition at a concentration of between 48% to 59%, 3% to 6%, 0.25% to 0.70%, and 0.6% to 3% respectively, all concentrations being expressed as % w/w.
  • the pharmaceutical composition comprises sodium croscarmellose, hydrogenated castor oil, lactose monohydrate and colloidal silicon dioxide.
  • Carglumic acid was obtained in pure crystalline form by reacting L- glutamic acid and potassium cyanate, according to known methods. Its chemical purity, calculated on anhydrous and solvent free basis, was assessed by means of HPLC at a wavelength detection of 205 nm. The product resulted 99.70% pure with no single impurities present in an amount greater than 0.03%.
  • XRPD demonstrated that the crystalline form corresponded to Form-I disclosed by Maddileti D., et al, in CrystEngComm, 2015, 17, 5252.
  • Linear solid-state detector Linear solid-state detector (Lynx Eye).
  • Pregelatinized starch (Starch 1500®; Colorcon, Eighenmann & Veronelli) Macrocrystalline cellulose: Avicel PH102
  • Lactose monohydrate Pharmatose DCL11 (Eigenmann e Veronelli SPA) Mannitol: Pearlitol 200SD (Roquette)
  • Stearic acid (Stearic acid 50, Carlo Erba)
  • Sodium croscarmellose Ac-Di-Sol (IMCD Italia SPA)
  • Crospovidone Kollidon® CL BASF
  • compositions comprising carglumic acid, lactose (i.e., anhydrous lactose or lactose monohydrate), sodium croscarmellose, colloidal anhydrous silica and hydrogenated castor oil resulted extremely stable.
  • lactose i.e., anhydrous lactose or lactose monohydrate
  • sodium croscarmellose i.e., anhydrous lactose or lactose monohydrate
  • colloidal anhydrous silica croscarmellose
  • colloidal anhydrous silica croscarmellose
  • colloidal anhydrous silica croscarmellose
  • hydrogenated castor oil resulted extremely stable.
  • 3 different grades of carglumic acid were used. Un-milled carglumic acid active ingredient (batch l) was milled by means of a hammer mill apparatus (Model RP 300, Nuova Guseo), applying variable hammer speed (i.e., 1500 or 3000 rpm)
  • composition of example 1 was obtained following a manufacturing process comprising the following steps ⁇
  • step d) of examples 1-6 the mixtures were sampled and titled for their content in carglumic acid in order to assess the influence of the particle size of carglumic acid ingredient as well as the impact of the nature of lactose filler on the homogeneity of the mixtures.
  • the sampling points were selected considering the biconical geometry of the tank and height of the blend in said tank. Two samples for each blend were extracted, one at the bottom of the tank, and one at its top.
  • the assays were performed through 10 ⁇ of sample solution injections.
  • compositions comprising anhydrous lactose (examples 4-6) proved difficulties to disintegrate in a satisfying manner, meanwhile lactose monohydrate gave rise to suitable disintegration time, similar or even better than the one reported in EP2777696. Stability studies
  • Impurity l 3 _ (i?, * 3 ⁇ 4 ) -[3-(aminocarbonyl)-2,5-dioxoimidazolidin-4-yl]-propanoic acid
  • the sample solution was prepared as previously described after having powdered the tablets.
  • the quantification of related substances was performed through 25 ⁇ of sample solution injections.
  • ARef Average area of Impurity 1 or Impurity 2 or Impurity 3 in the chromatograms of the Reference solution
  • ARef Average area of carglumic acid in the chromatogram of the
  • compositions comprising N- carbamyl-Zv- glutamic acid obtained through the process of the invention resulted extremely stable even in accelerated conditions for a period of at least three months.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne des formes posologiques de médicament stables à température ambiante élevée comprenant un activateur de Carbamoyl Phosphate synthétase 1 (CPS 1) sensible à la dégradation, notamment induite par l'humidité; et au moins un excipient pharmaceutiquement acceptable.
PCT/EP2018/054808 2017-02-28 2018-02-27 Composition pharmaceutique stable à température ambiante comprenant de l'acide carglumique Ceased WO2018158249A1 (fr)

Applications Claiming Priority (2)

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EP17000307.3 2017-02-28
EP17000307 2017-02-28

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WO2018158249A1 true WO2018158249A1 (fr) 2018-09-07

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020239882A1 (fr) * 2019-05-30 2020-12-03 Recordati Industria Chimica E Farmaceutica S.P.A. Formulation pharmaceutique pour l'acide carglumique
WO2021203703A1 (fr) * 2020-04-07 2021-10-14 中国科学院深圳先进技术研究院 Utilisation d'acide carglumique dans la préparation de médicaments pour la prévention et le traitement de coronavirus
CN116808013A (zh) * 2020-11-23 2023-09-29 武汉武药科技有限公司 卡谷氨酸原料药和卡谷氨酸固体制剂及其制备方法
WO2024136769A1 (fr) * 2022-12-20 2024-06-27 Santa Farma Ilac Sanayii A.S. Compositions de comprimés divisibles de manière homogène comprenant de l'acide carglumique

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2777696A1 (fr) 2013-03-15 2014-09-17 Navinta, llc. Préparation de formes posologiques pharmaceutiques stables
CN105056246A (zh) * 2015-08-18 2015-11-18 武汉武药科技有限公司 一种卡谷氨酸固体组合物及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2777696A1 (fr) 2013-03-15 2014-09-17 Navinta, llc. Préparation de formes posologiques pharmaceutiques stables
CN105056246A (zh) * 2015-08-18 2015-11-18 武汉武药科技有限公司 一种卡谷氨酸固体组合物及其制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
D. MADDILETI ET AL: "Polymorphism in anti-hyperammonemic agent N-carbamoyl-L-glutamic acid", CRYSTENGCOMM, vol. 17, no. 28, 1 January 2015 (2015-01-01), pages 5252 - 5265, XP055474622, DOI: 10.1039/C5CE00116A *
VALAYANNOPOULOS V. ET AL., ORPHANET JOURNAL OF RARE DISEASES, vol. 11, 2016, pages 32

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020239882A1 (fr) * 2019-05-30 2020-12-03 Recordati Industria Chimica E Farmaceutica S.P.A. Formulation pharmaceutique pour l'acide carglumique
WO2021203703A1 (fr) * 2020-04-07 2021-10-14 中国科学院深圳先进技术研究院 Utilisation d'acide carglumique dans la préparation de médicaments pour la prévention et le traitement de coronavirus
CN116808013A (zh) * 2020-11-23 2023-09-29 武汉武药科技有限公司 卡谷氨酸原料药和卡谷氨酸固体制剂及其制备方法
WO2024136769A1 (fr) * 2022-12-20 2024-06-27 Santa Farma Ilac Sanayii A.S. Compositions de comprimés divisibles de manière homogène comprenant de l'acide carglumique

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