EP3426231A1 - Compositions de nicergoline à libération modifiée - Google Patents

Compositions de nicergoline à libération modifiée

Info

Publication number
EP3426231A1
EP3426231A1 EP16753975.8A EP16753975A EP3426231A1 EP 3426231 A1 EP3426231 A1 EP 3426231A1 EP 16753975 A EP16753975 A EP 16753975A EP 3426231 A1 EP3426231 A1 EP 3426231A1
Authority
EP
European Patent Office
Prior art keywords
composition
nicergoline
hours
administered
pharmaceutically acceptable
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.)
Withdrawn
Application number
EP16753975.8A
Other languages
German (de)
English (en)
Inventor
Rajeev Singh Raghuvanshi
Bijay Kumar Padhi
Saurabh Srivastava
Amit Garg
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.)
KUNSHAN ROTAM REDDY PHARMACEUTICAL CO Ltd
Dr Reddys Laboratories Ltd
Original Assignee
KUNSHAN ROTAM REDDY PHARMACEUTICAL CO Ltd
Dr Reddys Laboratories Ltd
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 KUNSHAN ROTAM REDDY PHARMACEUTICAL CO Ltd, Dr Reddys Laboratories Ltd filed Critical KUNSHAN ROTAM REDDY PHARMACEUTICAL CO Ltd
Publication of EP3426231A1 publication Critical patent/EP3426231A1/fr
Withdrawn legal-status Critical Current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
    • A61K9/2022—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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • 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
    • A61K9/2027—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present application relates to a modified release composition comprising nicergoline or its pharmaceutically acceptable salt thereof.
  • Nicergoline is an ergot derivative used to treat senile dementia and other disorders with vascular origins. The product is indicated to prevent functional declines due to the sequelae of cerebral infarction and for the treatment of cognitive impairment in various forms of dementia.
  • Nicergoline and its active metabolites favorably influence the cerebral hemodynamic and metabolism. These activities are due to the a-lytic and myolytic activities and to the increase in glucose and oxygen consumption. Nicergoline undergoes rapid metabolism and is undetectable in serum by conventional bioassay methods. However the drug's two major metabolites 1 -methyl- 10-methoxy-dihydro-lysergol (MMDL) and 10- methoxy-dihydro-lysergol (MDL) are quite stable and are detectable.
  • MMDL 10-methoxy-dihydro-lysergol
  • MDL 10- methoxy-dihydro-lysergol
  • Nicergoline is absorbed in the intestinal tract and rapidly metabolized by hydrolysis, followed by partial demethylation and/or conjugation with glucuronic acid.
  • the administered dose is excreted in metabolized form, mainly in the urine and in a minor amount (10%) in the feces in a period of 3-4 days.
  • Nicergoline is used for the clinical treatment of acute and chronic cerebro-vascular metabolic disorders due to arteriosclerosis thrombosis, cerebral embolism and transient cerebral ischemia.
  • Nicergoline is currently marketed as Sermion® by Pfizer in most of the countries as tablet (5, 10, 15 & 30 mg), capsule (5 & 10 mg), injectable (4, 5 and 8 mg) liquid/drops (10 mg & 5 mg/ml), powder, and suspension (300 mg) dosage forms.
  • the CAS Registry Number for nicergoline is 27848-84-6 and the chemical name is [(8P)-10-methoxy-l,6-dimethylergolin-8-yl]methyl 5-bromopyridine-3-carboxylate; while its structural formula is:
  • Nicergoline is generally administered orally 2-3 times daily, for several months. This normally leads to adverse drug reactions such as hypotension, dizziness, stomach pain, thereby decreasing patient compliance.
  • modified release nicergoline composition would bring about remarkable advantages in terms of convenience for the patient and can improve the compliance. Moreover, it is known that from the therapeutic point of view a controlled- release composition allows to maintain more constant and lower blood concentrations, thus decreasing possible side-effects of nicergoline such as low blood pressure and dizziness, stomach disorders, hot flashes and skin redness.
  • Modified-release compositions are particular pharmaceutical compositions which have the ability to maintain a desired blood level of a medicament over an extended period of time by minimizing the peak-trough variations in plasma concentrations. It is therefore desirable to administer nicergoline through modified- release compositions, having improved dissolution properties and extended release profiles.
  • modified release nicergoline compositions which include EP0602619 Al, CN 101269035 and CN 101095663.
  • aqueous solubility of nicergoline is very low, it is difficult to prepare as modified-release compositions. It is often difficult to predict whether a particular modified-release composition will provide the desired release profile for a relatively insoluble compound.
  • the present application relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, which is convenient in dosing and offers less peak to trough plasma concentration fluctuation over the dosing interval.
  • the present application also relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, at least one rate-controlling polymer and one or more other pharmaceutically acceptable excipients.
  • the present application relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, at least one rate-controlling polymer and one or more other pharmaceutically acceptable excipients, wherein said composition provides therapeutically effective amount of nicergoline for a period of about 24 hours after oral administration.
  • the rate-controlling polymer comprises at least one hydrophilic polymer in an amount of from about 10% to about 70% by weight based on the total weight of the composition.
  • the present application relates to a modified release composition for once daily oral administration comprising about 30 mg to about 60 mg nicergoline or its pharmaceutically acceptable salt thereof, at least one rate-controlling polymer and one or more other pharmaceutically acceptable excipients, wherein said rate- controlling polymer comprises at least one hydrophilic polymer in an amount of from about 10%) to about 70%) by weight based on the total weight of the composition, wherein said composition provides therapeutically effective amount of nicergoline for a period of about 24 hours after oral administration.
  • composition of the present application may be in a monolithic matrix form and comprises intra-granular and extra-granular portions of components.
  • the present application relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, at least one rate-controlling polymer and one or more other pharmaceutically acceptable excipients, wherein said composition is in a monolithic matrix form and comprises intra-granular and extra-granular portions of components.
  • the composition of the present application is in a monolithic matrix form comprising at least one hydrophilic polymer present in both extra-granular portion and intra-granular portions, in a weight ratio of about 0: 1 to 1 : 1.
  • the composition of the present application exhibits at least one of the following dissolution profiles: (i) releases no more than about 30% of nicergoline in 2 hours, in 900ml of 0.1 N HCl solution, when tested in USP type 1 apparatus at a speed of 100 rpm and at a temperature of 37°C ⁇ 0.5°C, (ii) releases no more than about 30% of nicergoline in 2 hours, in 900ml of acetate buffer having pH of 4.5, when tested in USP type 1 apparatus at a speed of 100 rpm and at a temperature of 37°C ⁇ 0.5°C, (iii) releases no more than about 30% of nicergoline in 2 hours, in 900ml of phosphate buffer having pH of 6.8, when tested in USP type 1 apparatus at a speed of 100 rpm and at a temperature of 37°C ⁇ 0.5°C and (iv) releases no more than about 30% in 2 hours, no more than about 60% in 6 hours, and more than about 70% in
  • the composition of the present application when administered as single dose exhibits bioequivalence to a commercially available 10 mg nicergoline immediate release composition when administered thrice daily to a human subject in fasting conditions and said bioequivalence is established by: (i) a 90% Confidence Interval for mean AUQo-t), which is between 80% and 125%, and (ii) a 90% Confidence Interval for mean AUC(o- ⁇ ), which is between 80% and 125%.
  • composition of the present application when administered as a single dose to a human subject in the fasting and fed conditions have a mean AUCo-4 in the ratio of about 1 : 1.3.
  • the composition of the present application when administered as a single dose to a human subject in the fasting conditions have an exposure up to 8, 16 and 24 hours similar to an immediate release formulation comprising nicergoline 10 mg administered thrice daily in fasting conditions and have the mean AUCo-8, AUC0-16 and AUCo-24 in the ratio of about 1 : 1.
  • the composition of the present application when administered as a single dose to a human subject in the fasting conditions have a mean AUCo-8 to AUC0-2 in the ratio of about 1 : 0.03.
  • composition of the present application when administered as a single dose to a human subject in the fasting conditions have an average peak to trough plasma concentration ratio of simulated steady state profiles of about 1.66: 1.
  • composition of the present application when administered as a single dose to a human subject in the fasting conditions and in the fed conditions have a plasma concentration profile at 2 hours in the ratio of about 1 : 1.
  • the composition of the present application following a single dose oral administration to a human subject in fasting conditions exhibit at least one of the following plasma profiles: (i) about 6% of nicergoline absorption profile at 2 hours, (ii) about 20% of nicergoline absorption profile at 4 hours, (iii) about 42% of the nicergoline absorption profile at 8 hours and (iv) about 58% of the nicergoline absorption profile at 12 hours.
  • composition of the present application has delayed Tmax in both fasting and fed conditions when compared with first dose of the three divided doses of commercially available 10 mg nicergoline immediate release composition.
  • the composition has Tmax in the range of about 5-20 hours or about 8-15 hours or about 10-15 hours or about 13 hours.
  • the composition of the present application when administered to a human subject under fasting conditions provides steady state plasma profile and exhibits at least one of the following plasma profiles: (i) C ma x of about 5 ng/ml to 19 ng/ml of nicergoline or its detectable metabolites, (ii) C m in,ss is about 8 ng/ml to about 15 ng/ml of nicergoline or its detectable metabolites, (iii) C ma x,ss is about 13 ng/ml to about 26 ng/ml of nicergoline or its detectable metabolites, and (iv) C av g,ss is about 10 ng/ml to about 18 ng/ml of nicergoline or its detectable metabolites.
  • composition of the present application remains physically and chemically stable, upon storage at a temperature of about 40°C and relative humidity of about 75% for at least three months, and produces not more than 3% of total relative substances.
  • the composition upon storage at a temperature of about 40°C and relative humidity of about 75% for three months remains physically and chemically stable, produces not more than 3% of total relative substances, and produces less than 0.5% w/w of nicergoline N-Oxide compound having the structure of:
  • composition of present application is administered for the treatment of patients having acute or chronic cerebral metabolic-vascular disorders having cognitive loss and/ or dementia.
  • Figure. 1 shows dissolution profile of the nicergoline in Example-1 and Example-
  • Figure. 2 shows the plasma concentration of nicergoline metabolite MDL in pg/ml of Example- 1 and Example-2 over a period of 24 hours for oral administration of
  • composition containing 30 mg of nicergoline of the present application is provided.
  • FIG. 3 shows the plasma concentration of nicergoline metabolite MDL in pg/ml of Example- 1 and Example-2 over a period of 24 hours for oral administration of
  • composition containing 30 mg of nicergoline of present application given once under fasting condition vs. plasma concentration of nicergoline metabolite MDL for oral administration of reference product (Sermion®) tablets containing 10 mg of immediate release nicergoline (reference product) given t.i.d. under fasting condition.
  • reference product Semion®
  • Figure. 4 shows the plasma concentration of nicergoline metabolite MDL in pg/ml of Example- 1 and Example-2 over a period of 72 hours for oral administration of
  • composition containing 30 mg of nicergoline of the present application given once under fasting condition vs. plasma concentration of nicergoline metabolite MDL for oral administration of reference product (Sermion®) tablets containing 10 mg of immediate release nicergoline given t.i.d. under fasting condition.
  • reference product Semion®
  • salt includes derivatives of the disclosed compounds which are, within the scope of sound medical judgment, suitable for use in humans and lower animals without undue toxicity, irritation, allergic response and the like, which are well known in the art.
  • the salt can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the
  • pharmaceutically active substance having a freebase function, with a suitable organic acid or inorganic acid.
  • suitable organic acid or inorganic acid refers to pharmaceutically acceptable solvates, including hydrates, of such compounds and such salt.
  • composition for purposes of the present disclosure includes solid pharmaceutical products such as tablets, capsules, sachets, pills, or granules, containing a mixture of two or more compounds, elements or molecules. This may be matrix based compositions, reservoir based formulations, multi-particulate based formulations, multi-layer formulations, resin formulations, osmotic formulations, gastro- retentive formulations, etc.
  • the term "monolithic matrix” or “matrix” as used herein refers to a mixture containing at least one rate-controlling polymer, in which the drug is dispersed or dissolved or intermixed uniformly to have a homogenous or intimate mixture/ dispersion and capable of delivering the drug at a controlled rate for a period of time.
  • the overall release kinetics of the drug from the matrix is generally linear, such that a relatively constant amount of drug is released over the desired time period.
  • modified release By the term “modified release” (MR) it is meant that an active agent from a dosage form is released in controlled fashion in an environment over (throughout or during) an extended period of time.
  • modified release includes the terms like “extended release”, “controlled release”, “prolonged release”, “sustained release”, “slow release”, or alike terms as used in the pharmaceutical sciences.
  • excipient or "pharmaceutically acceptable excipient” means a component of a pharmaceutical product that is not having any pharmacological effect, such as a filler, diluent, carrier, etc.
  • the excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary use as well as human pharmaceutical use.
  • An "excipient” or a “pharmaceutically acceptable excipient” as used in the specification includes both one and more than one such excipients.
  • Cp plasma concentrations
  • fasting in t.i.d. dosing (is an abbreviation for "ter in die” which in Latin means three times a day) refers to fasting condition 2 hours before and after the dose administration.
  • the term "stability" as used herein includes both chemical stability and physical/polymorphic stability.
  • the term 'stability' is defined as the capacity of a drug substance or drug product to remain within the established specifications to maintain its identity, strength, quality and purity throughout the retest or expiration dating period.
  • the term 'chemical stability' means the tendency of drug to resist change or decomposition due to internal reaction, or due to the effects of oxygen, heat, light, pressure, etc.
  • the term 'related substances' (RS) or 'impurities' mean the degradation impurities or active ingredient process related impurities of drug material.
  • the term "AUC” refers to the area under the plasma concentration-time curve, as calculated by the log-linear trapezoidal rule over the complete dosing interval. The AUC (area under the curve) for a specified period is referred to as a "partial AUC" for the period.
  • C ma x refers to the highest plasma concentration of the drug attained within the dosing interval.
  • C ma x,ss refers to the highest plasma concentration (e.g., ng/ml) observed after repeated once daily administration at steady state.
  • C m in,ss refers to the trough plasma concentration (e.g., ng/ml) observed after repeated once daily administration at steady state.
  • C a vg,ss refers to the average plasma concentration at steady state.
  • T ma x refers to the time period which elapses after administration of a single dosage form at which the plasma concentration of the drug attains the highest plasma concentration of drug attained within the dosing interval.
  • shelf life is the time that finished products can be stored after manufacturing, during which the defined quality of a specified proportion of the product remains acceptable under expected (or specified) conditions of distribution, storage, and display.
  • the shelf life is established by the manufacturer of a product.
  • the term "stability testing” refers to tests conducted at specific time intervals and in various environmental conditions (e.g., temperature and humidity) to see if and to what extent a drug product degrades over its designated shelf life time. The specific conditions and time of the tests are accelerated, in order to mimic the conditions the drug product is expected to encounter over its shelf life.
  • RP-HPLC Reversed-phase high-performance liquid chromatography.
  • present application relates to a modified release composition of nicergoline or its pharmaceutically acceptable salt thereof.
  • the present application relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, at least one rate-controlling polymer and one or more other pharmaceutically acceptable excipients, wherein said composition provides therapeutically effective amount of nicergoline for a period of about 24 hours after oral administration.
  • the present application relates to a modified release composition for once daily oral administration comprising from about 30 mg to about 60 mg of nicergoline or its pharmaceutically acceptable salt thereof, at least one rate-controlling polymer and one or more other pharmaceutically acceptable excipients, wherein said composition provides therapeutically effective amount of nicergoline for a period of about 24 hours after oral administration.
  • the application relates to a modified release composition in a monolithic matrix form and delivers nicergoline in a controlled release manner.
  • the application relates to a modified release composition for once daily oral administration comprising about 30 mg to about 60 mg of nicergoline or its pharmaceutically acceptable salt thereof, at least one rate-controlling polymer and one or more other pharmaceutically acceptable excipients, wherein said composition is in a monolithic matrix form and provides therapeutically effective amount of nicergoline for a period of about 24 hours after oral administration.
  • the drug can be released predominantly by two mechanisms that include diffusion and/or degradation. Diffusion occurs when the drug is released either through pores in the polymer matrix or by passing between polymer chains of the matrix.
  • Diffusion occurs when the drug is released either through pores in the polymer matrix or by passing between polymer chains of the matrix.
  • the drug can be dispersed throughout the matrix, or localized within a reservoir adjacent to or within the matrix.
  • a reservoir system a reservoir of drug, for example, solid drug, dilute solution, or highly concentrated drug solution within a polymer matrix is surrounded by a controlled release material through which the drug is able to diffuse.
  • a degradable system the drug is released as the matrix is degraded in vivo. Drug can also be released by a combination of the two mechanisms.
  • the monolithic matrix described herein releases the drug by a combination of both diffusion and degradation.
  • the release rate can be controlled by varying the percent of rate-controlling polymer or varying the drug to polymer ratio.
  • the present application relates to a modified release composition for once daily oral administration comprising about 30 mg to about 60 mg of nicergoline or its pharmaceutically acceptable salt thereof, at least one rate-controlling polymer and one or more other pharmaceutically acceptable excipients, wherein said composition is in a monolithic matrix form and said nicergoline is intermixed uniformly with rate-controlling polymer to provide a homogenous or intimate mixture.
  • the application relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition is in a monolithic matrix form and comprises intra- granular and extra-granular portions.
  • the application relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition is in a monolithic matrix form comprising at least one hydrophilic polymer present in both extra-granular portion and intra-granular portions.
  • the application relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition is in a monolithic matrix form comprising at least one hydrophilic polymer present in at least in intra-granular or extra-granular portions.
  • the application relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, wherein the said composition comprises at least one hydrophilic polymer present in both intra-granular and extra-granular portions in a weight ratio of about 0: 1 to 1 : 1.
  • the rate-controlling polymer comprises at least one hydrophilic polymer in an amount of from about 10% to about 70% by weight based on the total weight of the composition.
  • the present application relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, at least one rate-controlling polymer and one or more other pharmaceutically acceptable excipients, wherein said rate-controlling polymer comprises at least one hydrophilic polymer in an amount of from about 10% to about 70% by weight based on the total weight of the composition.
  • the present application relates to a modified release composition for once daily oral administration comprising from about 30 mg to 60 mg of nicergoline or its pharmaceutically acceptable salt thereof, at least one rate-controlling polymer and one or more other pharmaceutically acceptable excipients, wherein said rate- controlling polymer comprises at least one hydrophilic polymer in an amount of from about 10%) to about 70%) by weight based on the total weight of the composition and said composition provides therapeutically effective amount of nicergoline for a period of about 24 hours after oral administration.
  • the present application relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition releases no more than about 30% of nicergoline in 2 hours, in 900ml of 0.1 N HCl solution, when tested in USP type 1 apparatus at a speed of 100 rpm and at a temperature of 37°C ⁇ 0.5°C.
  • the present application relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition releases no more than about 30% of nicergoline in 2 hours, in 900ml of acetate buffer having pH of 4.5, when tested in USP type 1 apparatus at a speed of 100 rpm and at a temperature of 37°C ⁇ 0.5°C.
  • the present application relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition releases no more than about 30% of nicergoline in 2 hours, in 900ml of phosphate buffer having pH of 6.8, when tested in USP type 1 apparatus at a speed of 100 rpm and at a temperature of 37°C ⁇ 0.5°C.
  • the composition of the present application may be subjected to changeover dissolution study which is performed by using USP apparatus I (Basket) with 100 RPM, and the dissolution methodology includes change over dissolution mediums i.e., one acid stage followed by two buffer stages.
  • in-vitro dissolution was carried out in acid stage (900 ml of 0. IN HCl solution, USP Type 1 apparatus at a speed of 100 rpm and 37°C) till 60 minutes, followed by first buffer stage (900 ml of acetate buffer solution having pH 4.5 at a speed of 50 rpm and 37°C) and second buffer stage (900 ml of phosphate buffer solution having pH 6.8 a speed of 100 rpm and 37°C).
  • a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition when subjected to a changeover dissolution study releases no more than about 30% in 2 hours, no more than about 60% in 6 hours, and more than about 70% in 10 hours of nicergoline.
  • a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition exhibits at least one of the following dissolution profiles:
  • the present application relates to a modified release composition for once daily oral administration comprising nicergoline 30 mg or its pharmaceutically acceptable salt thereof, wherein said composition exhibits bioequivalence to a commercially available 10 mg nicergoline immediate release composition when
  • the present application relates to a modified release composition for once daily oral administration comprising about 30 mg of nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition when administered as single dose exhibits bioequi valence to a commercially available 10 mg nicergoline immediate release composition when administered thrice daily to a human subject in fasting conditions and said bioequi valence is established by having 90% confidence interval (CI) of the relative mean AUQo-t) within 80.00% to 125.00%.
  • CI confidence interval
  • the present application relates to a modified release composition for once daily oral administration comprising about 30 mg of nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition when administered as single dose exhibits bioequi valence to a commercially available 10 mg nicergoline immediate release composition when administered thrice daily to a human subject in fasting conditions and said bioequi valence is established by having 90% confidence interval (CI) of the relative mean AUC(o- ⁇ ) within 80.00% to 125.00%.
  • CI confidence interval
  • the present application relates to a modified release composition for once daily oral administration comprising about 30 mg of nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition when administered as a single dose to a human subject in the fasting and fed conditions have a mean AUCo-4 in the ratio of about 1 : 1.3.
  • the present application relates to a modified release composition for once daily oral administration comprising about 30 mg of nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition when administered as a single dose to a human subject in the fasting conditions have an exposure up to 8, 16 and 24 hours similar to an immediate release formulation comprising nicergoline 10 mg
  • the application relates to a modified release composition for once daily oral administration comprising about 30 mg of nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition when administered as a single dose to a human subject in the fasting conditions have an average peak to trough plasma concentration ratio of simulated steady state profiles of about 1.66: 1.
  • the present application relates to a modified release composition for once daily oral administration comprising about 30 mg of nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition when administered as a single dose to a human subject in the fasting conditions have a mean AUCo-8 to AUC0-2 in the ratio of about 1 : 0.03.
  • the present application relates to a modified release composition for once daily oral administration comprising about 30 mg of nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition when administered as a single dose to a human subject in the fasting conditions and in the fed conditions have a plasma concentration profile at 2 hours in the ratio of about 1 : 1.
  • the present application relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof and at least one rate-controlling polymer, wherein the said
  • composition following single dose oral administration to a human subject in fasting conditions exhibit about 6% of nicergoline absorption profile at 2 hours.
  • the present application relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof and at least one rate-controlling polymer, wherein said composition following single dose oral administration to a human subject in fasting conditions exhibit about 20% of nicergoline absorption profile at 4 hours.
  • the present application relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof and at least one rate-controlling polymer, wherein said composition following single dose oral administration to healthy adult humans in fasting conditions exhibit about 42% of the nicergoline absorption profile at 8 hours.
  • the present application relates to a modified release composition for once daily oral administration to a human subject comprising nicergoline or its pharmaceutically acceptable salt thereof and at least one rate-controlling polymer, wherein said composition following single dose oral administration to healthy adult humans in fasting conditions exhibit about 58% of the nicergoline absorption profile at 12 hours.
  • the present application relates to a modified release composition for once daily oral administration to a human subject comprising nicergoline or its pharmaceutically acceptable salt thereof and at least one rate-controlling polymer, wherein said composition following single dose oral administration to healthy adult humans in fasting conditions exhibits at least one of the following plasma profiles:
  • the present application relates to a modified release composition for once daily oral administration comprising nicergoline 30 mg or its pharmaceutically acceptable salt thereof, wherein the composition exhibits a simulated mean C24/Cmax ratio of MDL of about 0.6: 1.0 when administered to healthy volunteers at steady- state (for 7 days).
  • the present application relates to a modified release composition for once daily oral administration comprising nicergoline 30 mg or its pharmaceutically acceptable salt thereof, wherein the composition exhibits a simulated steady state AUC, which is in the range from 80% to 125% of the AUC of the same amount of nicergoline administered as an immediate release formulation thrice daily.
  • the present application relates to a modified release composition for once daily oral administration to a human subject comprising nicergoline 30 mg, wherein said composition has delayed T ma x in both fasting and fed conditions when compared with first dose of the three divided doses of commercially available 10 mg nicergoline immediate release composition.
  • the present application relates to a modified release composition for once daily oral administration to a human subject comprising nicergoline 30 mg, wherein the said composition has T ma x in the range of about 5-20 hours.
  • the composition has Tmax of about 8-15 hours or about 10- 15 hours or about 13 hours.
  • the present application relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, wherein said dosage form has C ma x of about 5-19 ng/ml of nicergoline or its detectable metabolites when administered to human subjects in fasting condition.
  • the composition has Cmax of about 7-15 ng/ml or about 8- 15 ng/ml or about 8-10 ng/ml of nicergoline or its detectable metabolites.
  • the present application relates to a modified release composition for once daily oral administration to a human subject comprising about 30 mg of nicergoline, wherein said composition when administered to a human subject under fasting conditions provides steady state C m in,ss of about 8 ng/ml to about 15 ng/ml of nicergoline or its detectable metabolites.
  • the present application relates to a modified release composition for once daily oral administration to a human subject comprising about 30 mg of nicergoline, wherein said composition when administered to a human subject under fasting conditions provides steady state C ma x,ss of about 13 ng/ml to about 26 ng/ml of nicergoline or its detectable metabolites.
  • the present application relates to a modified release composition for once daily oral administration to a human subject comprising about 30 mg of nicergoline, wherein said composition when administered to a human subject under fasting conditions provides steady state C av g,ss of about 10 ng/ml to about 18 ng/ml of nicergoline or its detectable metabolites.
  • the present application relates to a modified release composition for once daily oral administration to a human subject comprising about 30 mg of nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition when administered to a human subject under fasting conditions provides steady state plasma profile and exhibits at least one of the following plasma profiles:
  • the rate-controlling polymer used may be hydrophilic, hydrophobic or combinations thereof.
  • the rate-controlling polymers are meant to control/ sustain the release rate of nicergoline.
  • hydrophilic polymers include, but are not limited to, cellulose derivatives such as
  • hydroxypropyl cellulose hydroxypropylmethylcellulose, hydroxyethyl cellulose, hydroxymethylcellulose, carboxymethylcellulose, methylcellulose, sodium carboxy methylcellulose or combinations thereof; non-cellulose polysaccharides (galactomannans, guar gum, carob gum, gum arabic, sterculia gum, agar, pregelatinized starch, alginates and the like); polyvinylpyrrolidone; polyvinyl acetate; copolymer of vinylpyrrolidone and vinyl acetate, polyalkylene glycols, acrylic acid polymers such as cross linked acrylic acid-based polymers; and a mixture comprising one or more of said materials.
  • non-cellulose polysaccharides galactomannans, guar gum, carob gum, gum arabic, sterculia gum, agar, pregelatinized starch, alginates and the like
  • polyvinylpyrrolidone polyvinyl acetate
  • hydroxypropylmethylcellulose polymers include those sold under the Trademark of METHOCEL® (DoW Chemical Corporation) or under the Trademark of METOLOSE® (Shin-Etsu).
  • the polymers can be of different grades and having varying viscosities.
  • hydrophobic polymers which can be used in the present application, include, but are not limited to, bees wax, glycol wax, carnauba wax,
  • the modified release composition for once daily oral administration of nicergoline further comprises one or more other pharmaceutically acceptable excipients such as one or more of diluents, binders, glidants, lubricants, colouring agents and coating materials.
  • Suitable examples of diluents which can be used in the present application include, but are not limited to, starches, lactose, mannitol, PearlitolTM SD 200, celluloses, confectioner's sugar, and the like. Different grades of lactose can be used and it includes, but are not limited to, lactose monohydrate, lactose DT (direct tabletting), lactose anhydrous, FlowlacTM (available from Meggle Products), PharmatoseTM (available from DMV), and others.
  • starch includes, but are not limited to, maize starch, potato starch, rice starch, wheat starch, pregelatinized starches (commercially available as PCS PC 10 from Signet Chemical Corporation) and Starch 1500, Starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starches
  • crystalline cellulose products include, but are not limited to,
  • binders include, but are not limited to, hydroxypropyl celluloses (KlucelTM LF), Nisso FIPC-L (Nippon Soda Co.
  • FIPC-EXF low viscosity hydroxypropyl methylcelluloses
  • FIPMC low viscosity hydroxypropyl methylcelluloses
  • polyvinylpyrrolidones or povidones e.g., grades PVP- K25, PVP-K29, PVP-K30, PVP-K90, etc.
  • copovidones e.g., PlasdoneTM S 630, a random copolymer of N- vinyl-2-pyrrolidone and vinyl acetate
  • powdered acacia gelatin, guar gum, carbomers (e.g. CarbopolTM products), water-soluble methylcelluloses, polymethacrylates, and starches.
  • Suitable examples of binders which can be used in the present application include, but are not limited to, carboxymethylcelluloses, hydroxyethylcelluloses, dextrin, gelatin, maltodextrin, polyethylene oxides, sodium alginate, hydroxypropylcelluloses, hydroxypropyl methylcelluloses, polyvinylpyrrolidones or povidone (e.g., PVP-K25, PVP-K29, PVP-K30, and PVP-K90D), powdered acacia, gelatin, guar gum, carbomers (e.g., a CarbopolTM product), methylcelluloses, polymethacrylates, and starches.
  • carboxymethylcelluloses hydroxyethylcelluloses, dextrin, gelatin, maltodextrin
  • polyethylene oxides sodium alginate
  • hydroxypropylcelluloses hydroxypropyl methylcelluloses
  • polyvinylpyrrolidones or povidone e.g
  • glidants or anti-sti eking agents can be used in the present application include, but are not limited to, talc, silica derivatives, colloidal silicon dioxide and the like or mixtures thereof.
  • Various lubricants that can be used in the present application include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, talc, glyceryl behenate, glyceryl monostearates, palmitic acid, carnauba wax, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, macrogols, and mixtures thereof.
  • Various useful colorants that can be used in the present application include any FDA approved colours including, but are not limited to, Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, food lake colorants, iron oxides and the like or mixtures thereof.
  • modified release compositions of the present application may be prepared by using any conventional techniques, not limiting to, dry granulation, wet granulation, direct compression, or combinations thereof.
  • the application relates to a modified release composition
  • a modified release composition comprising nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition is prepared by processes known in the art including, direct compression, dry granulation, wet granulation, fluidized bed granulation or combinations of such processes.
  • the present application relates to a process of preparing modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, comprising the steps of: a) blending the desired quantity of nicergoline with intra granular excipients to form uniform blend,
  • step (b) granulating the blend of step (a) with binder solution to form nicergoline granules, c) mixing the nicergoline granules of step (b) with extra granular excipients, d) compressing the mixture of step (c) into tablets, and
  • step (d) optionally film coating the tablets of step (d) to attain desired weight.
  • the present application may employ various granulation methods, for example, a) wet granulation methods, in which a binder and a solvent are added to a powder mixture and granulation is conducted, b) dry granulation methods, in which granulation is carried out by compacting/ decompacting or slugging/ deslugging a powder mixture, and c) melt granulation methods, in which a substance that melts on heating is mixed with an active agent and granulation is carried out.
  • wet granulation methods in which a binder and a solvent are added to a powder mixture and granulation is conducted
  • dry granulation methods in which granulation is carried out by compacting/ decompacting or slugging/ deslugging a powder mixture
  • melt granulation methods in which a substance that melts on heating is mixed with an active agent and granulation is carried out.
  • the solvent may be water or any of various organic solvents, for example, lower alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, methylene chloride, or any mixtures thereof.
  • mixing granulation methods employ planetary mixer, a screw mixer and the like; high-speed mixing granulation methods using a Henschel mixer, a Super mixer and the like; extruding granulation methods using a cylindrical granulator, a rotary granulator, a screw extruding granulator, a pellet mill type granulator and the like; wet high-shear granulation methods, fluidized-bed granulation methods, compression granulation methods, crushing granulation methods and spraying granulation methods can be used.
  • drying operation can be performed using an oven dryer, a fluidized bed dryer and the like; post drying crushing and sieving can be carried out to obtain granules or fine granules for use.
  • Equipment suitable for processing pharmaceutical compositions of the present application include any one or a combination of mechanical sifters, blenders, roller compactors, granulators (rapid mixer or fluid bed granulator), fluid bed dryers, compression machines, rotating bowls or coating pans, etc.
  • composition of present application may include one or more film coatings over the final composition.
  • composition of present application may be prepared as tablets, capsules, sachets, pills, or granules.
  • the application relates to a modified release composition for once daily oral administration comprising from about 30 mg to 60 mg of nicergoline or its pharmaceutically acceptable salt thereof nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition is packaged in a strip or a blister or a HDPE container optionally together with a desiccant and/or oxygen absorbent.
  • Suitable examples of packaging materials used in the present application include, but are not limited to, containers including lids, made of polyethylene and/or polypropylene and/or glass, and blisters or strips made of aluminium or high-density polypropylene, or polyvinyl chloride, or polyvinyl chloride coated with polyvinylidene dichloride, generally termed PVC/PVDC.
  • the packaging material optionally utilizes oxygen absorbers or desiccants with packaging material.
  • the present application provides a modified release composition comprising nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition remains physically and chemically stable, upon storage at a temperature of about 40°C and relative humidity of about 75% for at least three months.
  • the application provides a modified release composition comprising nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition upon storage at a temperature of about 40°C and relative humidity of about 75%) for three months produces not more than 3%> of total relative substances.
  • the present application relates to a modified release composition
  • a modified release composition comprising about 30 mg to 60 mg of nicergoline or its pharmaceutically acceptable salt thereof, at least one rate-controlling polymer and one or more other pharmaceutically acceptable excipients, wherein said composition upon storage at a temperature of about 40°C and relative humidity of about 75% for three months produces less than 0.5%) w/w of nicergoline N-Oxide compound having the structure of:
  • the present application relates to a process for producing a validated batch of a modified release composition containing nicergoline or its pharmaceutically acceptable salt thereof, comprising:
  • a) producing a batch of modified release composition comprising about 30 mg to 60 mg of nicergoline or its pharmaceutically acceptable salt thereof, at least one rate- controlling polymer and one or more other pharmaceutically acceptable excipients, b) performing stability testing with a sample of composition from the produced batch, c) determining the total amount of nicergoline N-Oxide compound present in the batch; and
  • validation of the composition of present application after stability testing is usually determined by a RP-HPLC method.
  • the present application relates to a modified release composition for once daily oral administration comprising nicergoline or its pharmaceutically acceptable salt thereof, wherein said composition is administered for the treatment of patients having acute or chronic cerebral metabolic-vascular disorders having cognitive loss and/ or dementia.
  • the present application relates to a method for treating patients having acute or chronic cerebral metabolic-vascular disorders having cognitive loss and/or dementia, comprising orally administering an once daily modified release composition comprising from about 30 mg to 60 mg of nicergoline or its pharmaceutically acceptable salt thereof, at least one rate-controlling polymer and one or more other pharmaceutically acceptable excipients, wherein said composition provides therapeutically effective amount of nicergoline for a period of about 24 hours after oral administration.
  • an once daily modified release composition comprising from about 30 mg to 60 mg of nicergoline or its pharmaceutically acceptable salt thereof, at least one rate-controlling polymer and one or more other pharmaceutically acceptable excipients, wherein said composition provides therapeutically effective amount of nicergoline for a period of about 24 hours after oral administration.
  • step (a) The mixture of step (a) is granulated using binder solution c)
  • the granules of step (b) were dried in a suitable drier and milled further to suitable size
  • step (c) The mixture of step (c) is further mixed with extra granular excipients and
  • step (d) The tablets of step (d) are further coating with opadry using suitable solvents.
  • Nicergoline N-oxide which is not present in pharmacopeia was identified.
  • This compound is chemically (6aR,9R,10aS) -9-(((5- bromonicotinoyl)oxy)methyl)-10a-methoxy-4,7-dimethyl-4,6,6a,7,8,9,10,10a- octahydroindolo[4,3-fg]quinolone 7-oxide compound and having the structure of

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Abstract

La présente invention concerne une composition à libération modifiée contenant de la nicergoline ou son sel pharmaceutiquement acceptable, au moins un polymère de régulation de la vitesse et un ou plusieurs autres excipients pharmaceutiquement acceptables. La présente invention concerne également une composition à libération modifiée qui procure des concentrations de plasma présentant une variation minimale, et qui permet un dosage pratique (c'est-à-dire des dosages moins fréquents).
EP16753975.8A 2015-07-08 2016-07-08 Compositions de nicergoline à libération modifiée Withdrawn EP3426231A1 (fr)

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CN201510397017.XA CN106333927A (zh) 2015-07-08 2015-07-08 修饰释放的尼麦角林组合物
PCT/IB2016/054111 WO2017006290A1 (fr) 2015-07-08 2016-07-08 Compositions de nicergoline à libération modifiée

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CN111904938A (zh) * 2020-05-15 2020-11-10 山东方明药业集团股份有限公司 一种尼麦角林片剂的制备方法
CN113081993A (zh) * 2021-04-15 2021-07-09 海南通用三洋药业有限公司 一种尼麦角林片剂的制备方法
CN113358790B (zh) * 2021-06-10 2022-11-11 河北嘉迈医药科技有限公司 一种尼麦角林及其制剂中有关物质的检测方法
CN113398089A (zh) * 2021-06-29 2021-09-17 海南通用三洋药业有限公司 一种尼麦角林胶囊的制备方法和尼麦角林胶囊

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CN1921839A (zh) * 2004-01-19 2007-02-28 兰贝克赛实验室有限公司 加巴喷丁的稳定缓释口服剂型及其制备方法
CN101095663A (zh) 2006-06-28 2008-01-02 黑龙江大学 尼麦角林缓释胶囊及其制备方法
CN101269035A (zh) 2008-05-16 2008-09-24 北京正大绿洲医药科技有限公司 尼麦角林缓释滴丸及其制备方法
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RU2018104691A (ru) 2019-08-09

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