WO2021171318A1 - Composition pharmaceutique transmucosale de lévocétirizine - Google Patents

Composition pharmaceutique transmucosale de lévocétirizine Download PDF

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Publication number
WO2021171318A1
WO2021171318A1 PCT/IN2021/050190 IN2021050190W WO2021171318A1 WO 2021171318 A1 WO2021171318 A1 WO 2021171318A1 IN 2021050190 W IN2021050190 W IN 2021050190W WO 2021171318 A1 WO2021171318 A1 WO 2021171318A1
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Prior art keywords
levocetirizine
sublingual
stable
composition
tablet
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PCT/IN2021/050190
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English (en)
Inventor
Ulhas Dhuppad
Babasaheb Aware
Sainath Digambar KADAM
Akhilesh Sharma
Chirag Mahendrabhai TELI
Amol AIWALE
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Alkem Laboratories Ltd
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Publication of WO2021171318A1 publication Critical patent/WO2021171318A1/fr

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to a stable transmucosal pharmaceutical composition of Levocetirizine or pharmaceutically acceptable salt thereof and and processes for preparing thereof.
  • This invention more particularly relates to the method of such composition for alleviating associated symptoms of the allergic diseases such as allergic rhinitis and urticaria requiring fast onset of action.
  • Allergic Rhinitis represents the most common chronic airway disease in the world affecting many individuals.
  • Symptoms include sneezing, runny nose and red, watery, itchy eyes and like which significantly impair the quality of life with the negative effects apparent in all areas of daily living; specifically difficulties with daily activities, reduced sleep quality, daytime fatigue, impaired learning, impaired cognitive functioning, decreased long time productivity, decreased feeling of mental wellbeing, so it impairs work productivity and school performance.
  • the AR can be considered to be a risk factor for the development of asthma and which is based on duration of symptoms of AR and their severity.
  • Urticaria is also known as hives and it is an outbreak of swollen, pale red bumps or plaques (wheals) on the skin that appear suddenly either as a result of the body's reaction to certain allergens, or for unknown reasons. Hives usually cause itching, but may also burn or sting. If the condition has a duration of less than 6 weeks, it is acute. If it persists for more than 6 weeks, or recurs, it is chronic. Angioedema is often associated with chronic urticaria. Symptoms of the disorder may endure for several months or years. The most frequent causes of acute urticaria, which may affect up to 15%— 25% of all individuals at some stage in their lives, are viral infections (especially affecting the upper respiratory tract), food allergies, and drug adverse reactions. Physical effects, systemic disease, or long-term infection may also lead to urticaria/angioedema.
  • Histamine has a key role in the pathophysiology of allergic inflammation. After exposure to an allergen, specific antibodies of the IgE type are produced in genetically predisposed individuals. Because of the central role of histamine in allergic responses, many allergic conditions are treated with antihistamines, including allergic rhinitis and urticaria.
  • Levocetirizine is the treatment of choice for the relief of symptoms of seasonal allergic rhinitis (SAR), perennial allergic rhinitis (PAR), and chronic idiopathic urticaria (CIU) in adults and children aged more than or equal to 6 years.
  • XYZAL Levocetirizine tablet
  • XYZAL Levocetirizine solution
  • Levocetirizine tablet (XYZAL) and Levocetirizine solution (XYZAL) pharmaceutical preparations have T max at 0.9 hours and 0.5 hours respectively.
  • the plasma half-life of oral tablet and oral solution in adult healthy subject is about 8 to 9 hours and the mean oral total body clearance for Levocetirizine is approximately 0.63 mL/kg/min.
  • Levocetirizine 5 mg in controlling pollen-induced symptoms has been observed at 1-hour post drug intake.
  • the extent of metabolism of Levocetirizine in humans is less than 14% of the dose. So there is 14% loss of drug because of liver metabolism.
  • Metabolic pathways include aromatic oxidation, N and O-dealkylation, and taurine conjugation. Dealkylation pathways are primarily mediated by CYP 3A4 while aromatic oxidation involves multiple and/or unidentified CYP isoforms.
  • US2006083786 relates to the taste masked pharmaceutical composition comprising Levocetirizine for the medical treatment of allergic conditions.
  • IN1398/DEL/2007 discloses the mouth dissolving tablet of Levocetirizine and its use for the method of treatment of seasonal and perennial allergic rhinitis.
  • CN102716099B discloses chewable tablet composition for the alleviating allergy symptoms caused by allergic diseases, such as: allergic rhinitis (including allergic eye symptoms), urticaria, angioneurotic edema, contact dermatitis, insect bite, allergic diseases such as dermatitis of the skin and mucous membranes.
  • allergic diseases such as: allergic rhinitis (including allergic eye symptoms), urticaria, angioneurotic edema, contact dermatitis, insect bite, allergic diseases such as dermatitis of the skin and mucous membranes.
  • Sublingual tablet dosage form comprising montelukast sodium and levocetirizine dihydrochloride which was prepared by direct compression method using SSG, CP and CCS as superdisintegrants.
  • the sublingual tablet dosage form comprising Montelukast and Levocetirizine HCL further were evaluated for the physicochemical parameters.
  • Both prior art references P. Choudhary et al. and Apama C. et al. are silent on the specific characterisation of sublingual tablet dosage form.
  • the disclosed sublingual tablet dosage form of Levocetirizine would require 60 minutes for maximum drug release.
  • many of the available marketed sublingual tablet preparations such as Saphris provides maximum drug release within 5 min.
  • transmucosal pharmaceutical formulations which provide a rapid onset of action for faster relief of the symptoms associated with allergic rhinitis compared to the currently available therapies.
  • Transmucosal route of administration has faster rate of absorption directly into systemic circulation. This also avoids first pass metabolism & thereby improves overall drug concentration achieved.
  • It is an object of the present invention to provide a transmucosal pharmaceutical composition comprising Levocetirizine or pharmaceutical acceptable salt thereof in association with the pharmaceutically acceptable excipients.
  • It is another object of the invention to provide a sublingual pharmaceutical composition comprising Levocetirizine or pharmaceutical acceptable salt thereof in association with the pharmaceutically acceptable excipients and process for preparing thereof.
  • It is another object of the present invention to provide sublingual pharmaceutical composition comprising Levocetirizine or pharmaceutically acceptable salt thereof which has a rapid onset of action. It is another object of the invention to provide a Sublingual tablet composition comprising
  • It is another object of present invention to provide a sublingual film composition comprising
  • Another object of the present invention is to provide transmucosal composition of Levocetirizine prepared within a pH range of 3 -9 using suitable buffering agents.
  • the present invention relates to the pharmaceutical composition for transmucosal administration of Levocetirizine or pharmaceutically acceptable salt thereof in association with pharmaceutically acceptable excipients.
  • the pharmaceutical composition for transmucosal administration comprising Levocetirizine or salt thereof in association with the pharmaceutically acceptable excipients characterised in that the composition has a rapid onset of action compared to the marketed preparations.
  • the present invention relates to the sublingual dosage form of Levocetirizine or pharmaceutically acceptable salt thereof in association with the pharmaceutically acceptable excipients.
  • the present invention relates to the sublingual tablet dosage form comprising Levocetirizine or pharmaceutically acceptable salt thereof in association with the pharmaceutically acceptable excipients.
  • the present invention relates to the sublingual film dosage form comprising Levocetirizine or pharmaceutically acceptable salt thereof in association with the pharmaceutically acceptable excipients.
  • the present invention relates to the method of preparation of the fast acting pharmaceutical composition for transmucosal administration comprising Levocetirizine or pharmaceutically acceptable salt thereof in association with the pharmaceutically acceptable excipients.
  • the present invention relates to the method of preparation of the sublingual tablet dosage form of Levocetirizine or pharmaceutically acceptable salt thereof in association with the pharmaceutically acceptable excipients.
  • the present invention relates to the method of preparation of the sublingual film dosage form of Levocetirizine or pharmaceutically acceptable salt thereof in association with the pharmaceutically acceptable excipients.
  • the present invention relates to the method of using such composition for alleviating associated symptoms of allergic diseases such as allergic rhinitis and urticaria requiring the rapidity of the response.
  • the present invention relates to the sublingual pharmaceutical composition of Levocetirizine prepared within a pH range of 3 - 9 using suitable buffering agents.
  • the present invention relates to the transmucosal composition of Levocetirizine or salt thereof in association with sweetening and flavouring agents to provide the composition without unpleasant taste.
  • Levocetirizine dihydrochloride [(R)-[2-[4-[(4-chlorophenyl) phenylmethyl]-l- piperazinyl] ethoxy]] acetic acid dihydrochloride is an orally active Hl-receptor antagonist. It is the R enantiomer of cetirizine hydrochloride, a racemic compound with antihistaminic properties.
  • the empirical formula of levocetirizine dihydrochloride is C 21 H 25 ClN 2 0 3 ⁇ 2HCl.
  • the molecular weight is 461.82 and the chemical structure is shown below:
  • H-receptor histamine receptors
  • H1R Hl-receptor
  • histamine release has many clinical manifestations related to the numerous cells that can be involved in the allergic reaction, e.g., itch, pain, increase of the vascular permeability with edema and hypotension, flushing, headache, tachycardia, bronchoconstriction, reduction in the atrioventricular node conduction time, and impairment of the CNS functions. Additionally, histamine promotes the release of other mediators from immune-competent cells; it increases the cellular adhesion molecule expression, the chemotaxis of eosinophils and neutrophils, the antigen-presenting cell capacity, and other mechanisms of inflammation
  • Levocetirizine the active enantiomer of cetirizine, is an antihistamine; its principal effects are mediated via selective inhibition of HI receptors.
  • Levocetirizine shows a high affinity and a long-lasting occupancy of the H1R; therefore, the strong and sustained pharmacological inhibition of the H1R present on endothelial and vascular smooth muscle cells prevents vasodilatation, edema formation and mucus hypersecretion (Expert Opin. Pharmacother. (2009) 10(14)).
  • Levocetirizine has a potent and selective antihistamine activity. It has favourable pharmacodynamics and the pharmacokinetics characteristics e.g., high bioavailability and receptor occupancy, limited tissue distribution and a low degree of metabolism. In addition to the anti-histaminic activity, Levocetirizine also has the anti-inflammatory activity that are observed at clinically relevant concentrations and which may enhance its therapeutic benefit.
  • Levocetirizine has a half-life of 8-9 hours and oral total body clearance of about 0.63 mL/kg/min. Peak concentrations are typically 270 ng/ml and 308 ng/ml following a single and a repeated 5 mg O.D. dose, respectively. The onset of action of Levocetirizine 5 mg in controlling pollen-induced symptoms has been observed at 1-hour post drug intake. The extent of metabolism of Levocetirizine in humans is less than 14% of the dose.
  • the accumulation ratio following oral administration is 1.12 with steady state achieved after 2 days. Peak concentrations are typically 270 ng/ml ad 308 ng/ml following a single and a repeated 5 mg once daily dose respectively. Food had no effect on the extent of exposure (AUC) of the Levocetirizine tablet, but Tmax was delayed by about 1.25 hours and Cmax was decreased by about 36% after administration with a high fat meal. In adults, peak plasma concentrations are achieved 0.9 hour after administration of the oral tablet and it is achieved 0.5 hour after administration of oral solution.
  • Metabolic pathways include aromatic oxidation, N- and O -dealkylation, and taurine conjugation. Dealkylation pathways are primarily mediated by CYP3A4 while aromatic oxidation involves multiple and/or unidentified CYP isoforms. First pass metabolism greatly reduces the bioavailability of the drug.
  • Levocetirizine like Levocetirizine tablet and Levocetirizine solution (XYZAL) have Tmax longer than 0.5 hours which will lead to delay in onset of response. Delay in onset of action will eventually affects the on demand antiinflammatory responses required in many allergic conditions like Allergic Rhinitis, Urticaria and like.
  • the present invention provides transmucosal pharmaceutical compositions comprising Levocetirizine or pharmaceutically acceptable salt thereof in association with pharmaceutically acceptable excipients thereof characterised in that the composition of the present invention provides 80% drug release within 5 minute & thereby achieve Tmax at 0.25 to 0.5 hours. And therefore providing faster onset of action within 0.5 hours.
  • the transmucosal pharmaceutical composition of present invention provides improved and faster alleviation of symptoms associated with allergic diseases like allergic rhinitis and urticaria.
  • the present invention provides transmucosal pharmaceutical composition of Levocetirizine with lesser side effects compared to marketed oral Levocetirizine formulations.
  • composition in pharmaceutics, “is the process in which different chemical substances, including the active drug, are combined to produce a final medicinal product”.
  • stable refers to chemical stability of Levocetrizine in solid dosage forms wherein there is no change in assay values and dissolution and/or the total impurity remains less than 2%, when the dosage form is kept at 400C /75 %RH and 300C /75 % RH or 25°C ⁇ 2°C/60% ⁇ 5% RH for 6 months.
  • Transmucosal refers to “the route of administration in which the drug is diffused through the mucous membrane. This can refer to inhalation, nasal, sublingual, vaginal, rectal, or ocular routes”.
  • Onset of action means “the time required after administration of a drug for a response to be observed.”
  • Onset of action refers to the duration of time it takes for a drug's effects to come to prominence upon administration. With oral administration, it typically ranges anywhere from 20 minutes to over an hour, depending on the drug in question. Other methods of ingestion such as smoking or injection can take as little as seconds to minutes to take effect.
  • the determination of the onset of action is not completely dependent upon route of administration. There are several other factors that determine the onset of action for a specific drug, including drug formulation, dosage, and the patient receiving the drug.
  • the fast acting dosage form for rapid onset of action may be provided by transmucosal delivery dosage form.
  • the transmucosal drug delivery dosage form available in prior art are pulmonary transmucosal drug delivery, nasal transmucosal drug delivery and oral transmucosal drug delivery.
  • the oral transmucosal drug delivery may be provided, for example, by way of the spray, for example by spraying in oral cavity or under the tongue, or by way of rapid melting tablet formulations or by way of placing the dosage form under tongue or effervescent tablet formulations all of which are known to the skilled person in the art.
  • the present invention provides sublingual composition of Levocetirizine or pharmaceutically acceptable salt thereof.
  • the present invention provides pharmaceutical composition for sublingual administration comprising Levocetirizine or pharmaceutically acceptable salt thereof.
  • Sublingual literally means ‘below the tongue’.
  • sublingual dosage form refers to the dosage form that is to be administered via submucosal route that is below the tongue such that the active is absorbed via the blood vessel below and not via the digestive track absorption.
  • the sublingual mucosa is highly vascularized having good absorption properties as compared to other mucosal epithelial cell layer, the therapeutic substance gets rapidly absorbed through it so as to allow direct access to systemic circulation and thereby enabling rapid onset of action while overcoming problems associated with other marketed available oral administrations.
  • the present invention provides Sublingual Levocetirizine compositions characterised in that the compositions have a rapid onset of action and therefore provides a faster onset of relief compared to other anti-histaminic.
  • the present invention provides the sublingual Levocetirizine composition characterised in that the sublingual Levocetirizine composition of the present invention is advantageous over the available marketed preparation and offers benefits by reducing time for onset of action, by shifting AUC & T ma x toward left.
  • Sublingual Levocetirizine composition of the present invention provide rapid onset of action over marketed oral preparations.
  • composition of the present invention bypasses first pass metabolism because the sublingual route allow drug to be absorbed directly into systemic circulation.
  • Ease of administration for the patients who have difficulty in swallowing such as paediatric, geriatric patients and psychiatric patients, patients who are mentally ill, disabled and uncooperative is another advantage of the sublingual composition of the present invention.
  • the sublingual levocetirizine composition of the present does not require water for intake and thus provides an alternative to patients with swallowing disorders as a result of extremities and dysphagia and to patients suffering from nausea, such as those patients receiving chemotherapy.
  • the sublingual dosage form of the present invention is more stable, durable and dissolves rapidly compared to marketed conventional dosage forms.
  • the sublingual Levocetirizine composition of the present invention has an improved dosing accuracy; specifically sublingual tablet and film composition of the present invention not only ensures accurate administration of drugs but also can improve compliance due to intuitive nature of the dosage form and its inherent ease of administration.
  • the sublingual Levocetirizine composition of the present invention can be unobstructive and can be designed to leave minimal or no residue in the mouth after administration and also provides a pleasant mouth feel.
  • the present invention provides sublingual Levocetirizine compositions characterised in that the compositions have a rapid onset of action as compared to other available marketed preparations of Levocetirizine.
  • the present invention provides sublingual Levocetirizine compositions having Tmax at 0.25 to 0.5 and thereby providing faster onset of action within 0.5 hours; preferably within 0.4 hours.
  • Tmax at 0.25 to 0.5
  • Cmax was decreased by 36%.
  • the Levocetirizine sublingual composition bypass the first pass metabolism as the sublingual route allow the drug to be absorbed directly into systemic circulation. Therefore food will not affect Cmax and Tmax of the levocetirizine sublingual composition of the present invention.
  • the invention is suitable for compositions selected from but not limited to sublingual tablet, sublingual film, sublingual spray, sublingual drops and the like.
  • Sublingual tablet refers to “one that dissolves when held beneath the tongue, permitting direct absorption of the active ingredient by the oral mucosa”.
  • Sublingual film refers to “dissolving film or oral drug strip to administer drug via sublingual route”.
  • the present invention provides Sublingual Levocetirizine compositions characterised in that the composition bypass the first pass metabolism.
  • the present invention is directed to methods of using such composition for the treatment of allergic rhinitis and Urticaria.
  • Levocetirizine sublingual composition of the present invention provides faster onset of relief from the associated symptoms of allergic diseases like allergic rhinitis and urticaria.
  • the present invention provides a method for treating a patient suffering from allergic rhinitis and urticaria comprising administering a therapeutically effective amount of Levocetirizine in sublingual composition.
  • the present invention is directed to method of preparation of sublingual dosage form comprising Levocetirizine or pharmaceutically acceptable salt thereof in association with pharmaceutically acceptable excipients.
  • the Levocetirizine sublingual tablet composition of the present invention can be produced by the process available in prior art references.
  • the process available in the prior art references for preparation of tablet dosage form are direct compression, aqueous granulation, Non aqueous granulation, dry granulation (Roll compaction).
  • the Levocetirizine sublingual film composition of the present invention can be prepared by the methods such as Solvent casting, Hot- melt extrusion, Semisolid casting.
  • Levocetirizine or pharmaceutically acceptable salt thereof is converted to polymorphic form suitable for incorporation in sublingual film composition.
  • the Levocetirizine sublingual film composition prepared by solvent casting method wherein the water soluble ingredients dissolved in water and other suitable solvents used for dissolving polymers and to form a clear solution; both the formed solutions then mixed and casted as film on plain surface and further dried to get the film. The obtained film then cut in the desired size.
  • the Levocetirizine sublingual film composition is prepared by the Hot-melt extrusion method.
  • the solid carrier mixed properly and added in the extruder having heater to melt the mixture.
  • the melt mixture is then added to the selected shape dies and allowed to cool.
  • the cooled film were then removed from dies and was cut in desired size of film.
  • the Levocetirizine sublingual film composition is prepared by Semisolid casting method.
  • the Levocetirizine and other water soluble ingredients were added in suitable in quantity of purified water. Suitable solvent used to dissolve insoluble polymer. Both formed solutions then mixed with addition of the plasticizer to get like mass. Then formed mass is then casted into film in heat controlled drums or dryer. The obtained films then cut in desired size.
  • the present invention provides pharmaceutical composition characterised in that the composition comprises a therapeutically effective amount of Levocetirizine in the range of 1% to 5%.
  • sublingual compositions of Levocetirizine are administered sublingually that is below the tongue.
  • the present invention is particularly suitable for the sublingual tablet dosage form of Levocetirizine or pharmaceutically acceptable salt thereof comprising diluents, disintegrants, buffering agents, sweetening agents, flavours, glidents/lubricants, permeation enhancers and the like.
  • the present invention is particularly suitable for the sublingual film dosage form of Levocetirizine or pharmaceutical acceptable salt thereof comprising mucoadhesive polymers, plasticizers, surfactant, buffers, sweetening agents, flavours, salvia stimulating agents, colouring agents and the like.
  • Levocetirizine molecule has three ionizable moieties resulting three pKa values, for carboxylic acid moiety Pka 2.19 and for Nitrogen moiety Pka 2.80 and 8.0.
  • the inventors of the present invention have found that by adjusting the pH of the composition in the range of 3 -9 will provide maximum absorption of Levocetirizine.
  • the pH of the saliva is 6. 0; this favours absorption of the drug which remain unionised. Therefore pH range of the Sublingual compositions is important for better absorption of drug through oral mucosa.
  • the present invention provides sublingual composition of Levocetirizine prepared within a pH range of 3-9 which provides enhanced absorption of Levocetirizine.
  • the invention is directed to sublingual Levocetirizine pharmaceutical compositions characterised in that the composition provides better patient compliance which is devoid of any unpleasant taste.
  • the suitable diluents that may be use for the formulation of the invention are microcrystalline cellulose, Lactose monohydrate, Mannitol, dicalcium phosphate, Starch 1500, modified starch, silicified microcrystalline cellulose, calcium phosphate powder, screened sucrose carboxymethylcellulose sodium, coprocessed lactose, sorbitol, maltitol, dextrin, xylitol and like.
  • Suitable disintegrants selected from but not limited to crospovidone, croscarmellose sodium, Sodium starch glycolate, alginic acid, low substituated hydroxypropyl cellulose.
  • buffering agents include but not limited to carbonates (i.e., sodium bicarbonate, sodium carbonate), citrates, sodium citrate, gluconates, phosphate, tartrates or its other salts.
  • sweetening agent examples include but not limited to sorbitol, xylitol, mannitol, xylose, ribose, glucose, mannose, sucralose, saccharin powder, sodium saccharin, aspartame, sodium cyclamate, sucrose, dextrose, maltitol solution or any other saccharides.
  • Suitable flavours may be use for formulation of invention but not limited to cherry, chocolate mint, citrus, berry, vanilla, butterscotch, mint, peppermint flavour, grape flavour, mixed fruit flavour, banana flavour and like.
  • glidents/lubricants include but not limited to colloidal silicon dioxide, magnesium stearate, sodium sterayl fumarate, talc, sucrose stearate and like.
  • the formulations of the present invention may comprise one or more saliva stimulating agents.
  • the saliva stimulating agent increases the rate of secretion of saliva that would aid in the faster disintegration of the rapid dissolving formulations.
  • acids which are used in the preparation of food can be utilized as salivary stimulating agents. Citric acid, malic acid, lactic acid, ascorbic acid and tartaric acid are the few examples of salivary stimulants, citric acid being the most preferred amongst them. The acceptable acids will increase patient.
  • the formulations of the present invention may also comprise mucoadhesive polymers include but not limited to Cellulose derivatives, pullulan, gelatin, hydroxylpropylmethyl cellulose, Hydroxyethyl cellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyvinyl alcohol, sodium alginate, xanthum gum, methyl methacrylate co- polymer, hypromellose and the like.
  • the formulations of the present invention may also comprise plasticizers including but not limited to Glycerine, propylene glycol, polyethylene glycol, sorbitol, triacetin, dibutylpthalate, triethyl citarate and the like.
  • the formulations of the present invention herein may comprises one or more permeation enhancers.
  • Permeation enhancers are substances that reversibly increase the permeability of the mucosal epithelium to allow the transport of the drug to the blood circulation/lymph system.
  • Permeation enhancers modify the barrier properties of the absorbing cell layer and thus improve trans-membrane flux. These compounds act by increasing cell membrane fluidity, extracting intercellular lipids, interacting with epithelial protein domains, altering mucus structure and rheology.
  • the buccal penetration can be enhanced by use of various types of permeation enhancers such as bile salts, surfactants, fatty acids and derivatives, glycerides, salicylates, polymers, chelators, ethanol, cyclodextrins, enzyme inhibitors and chitosan etc.
  • permeation enhancers such as bile salts, surfactants, fatty acids and derivatives, glycerides, salicylates, polymers, chelators, ethanol, cyclodextrins, enzyme inhibitors and chitosan etc.
  • bile salts include but not limited to Sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium fusidate, sodium glycodeoxycholate, sodium taurodihydrofusidate.
  • Suitable surfactants that may be use for the formulation of the invention but not limited to sodium lauryl sulfate, Brij l-35, lysophosphatidylcholine, dioctyl sodium sulfosuccinate, sodium dodecyl sulphate, laurenth-9, polysorbate-80, polyethyleneglycol-8- laurate, glyceryl monolaurate.
  • fatty acids and derivatives includes but not limited to Sorbitan laurate, sodium caprate, sucrose palmitate, lauroyl choline, sodium myri state, palmitoyl carnitine.
  • colouring agents include but not limited to FD&C colors, natural coloring agent, pigments such titanium oxide, zinc dioxide and the like.
  • glycerides include but not limited to Phospholipids, monohexanoin, medium chain glycerides.
  • Suitable chelators and salicylates include but not limited to Ethylene diamine tetraacetate (EDTA), disodium EDTA, Salicylic acid, sodium methoxysalicylate, aspirin and the like.
  • Suitable polymers that may be use for the formulations of invention but not limited to Chitosan, polycarbophil, sodium carboxymethylcellulose and their derivatives. Further the formulation of present invention may also comprise other agents that may act as a permeation enhancers includes but not limited to Zonula occluden toxin, poly-l-arginines, soybean derivative glucosides, citicholine, a-acid derivatives, Azonel, cyclodextrins, benzalkonium chloride, phenothiazines, nitric acid donors, menthol.
  • the stable transmucosal pharmaceutical composition of Levocetirizine or salt thereof for sublingual administration comprises Levocetirizine dihydrochloride in an amount 1-6%, Lactose monohydrate in an amount of 40-50%, Mannitol in an amount of 30- 40%, Stearic acid in an amount of 1-10%, Crospovidone in an amount of 1-10%, Sucralose in an amount of 1-3%, Peppermint flavor in an amount of 1-3%, Sodium citrate anhydrous in an amount of 1-3% and Magnesium stearate in an amount of 1-3%.
  • the stable transmucosal pharmaceutical composition of Levocetirizine or salt thereof for sublingual administration comprises Levocetirizine Dihydrochloride in an amount of 1-6%, Lactose monohydrate in an amount of 40-50%, mannitol in an amount of 30- 40%, stearic acid in an amount of 1-10%, crospovidone in an amount of 1-10%, sucralose in an amount of 1-3%, peppermint flavor in an amount of 1-3%, sodium citrate anhydrous in an amount of 1-3%, sodium caprate in an amount of 1-10% and magnesium stearate in an amount of 1-3%.
  • the sublingual dosage form having rapid onset of action relates to the sublingual dosage form which has T max at less than 0.5 hours, preferably at 0.4 hours.
  • the sublingual dosage form of the present invention provides the maximum plasm concentration of the drug within 0.5 hours of the administration, preferably within 0.4 hours.
  • T max relates the amount of time that a drug is present at the maximum concentration in serum.
  • the maximum plasm concentration of the drug at specific amount of the time can be determined by the methods available in the prior art references.
  • the available marketed sublingual dosage form such as Saphris which has rapid onset of action, provides maximum release of the drug within 1-10 minutes.
  • the inventors of the present invention have found that for the rapid onset of action the dosage form must provide release of at least 80% of drug within 5 minutes, preferable within 3 minutes.
  • the sublingual dosage form of the present invention when measured in a standard in-vitro dissolution type II apparatus according to the United states pharmacopeia, using a phosphate buffer at pH 6.8 (USP) as a dissolution medium provides release of at least 80% of the active ingredient within 4 minutes, more preferably within 3 minutes.
  • USP phosphate buffer at pH 6.8
  • release mean the active ingredient is released from the formulation and dissolved in dissolution medium.
  • the formulations of the present invention can be produced by the process available in prior art references.
  • the process available in the prior art references for preparation of oral tablet dosage form are direct compression, aqueous granulation, Non aqueous granulation, dry granulation (Roll compaction).
  • step 1 The material of step 1 was blended for 15 min in the blender then lubrication was done by addition of magnesium stearate in the blender.
  • the inventors of the present invention have evaluated the exemplified sublingual tablet composition of Levocetirizine for In-process control parameters like Hardness test, Disintegration time, pH of the tablet in 5ml water. The result is mentioned in Tablet 10 below.
  • Table 10 The in-vitro dissolution profile for Example 5 of Levocetirizine sublingual tablet dosage form of the present invention is shown below in Table 11 :
  • the sublingual tablet dosage form of the present invention when measured in a standard in-vitro dissolution type II apparatus according to the United states pharmacopeia, using a phosphate buffer at pH 6.8 (USP) as a dissolution medium provides release of at least 80% of the active ingredient within a minutes, preferably within 4 minutes, more preferably within 3 minutes.
  • USP phosphate buffer at pH 6.8
  • the formulation of the present invention can be produced by the process available in prior art references.
  • the process available in the prior art references for preparation of sublingual film dosage form are solvent casting, hot- melt extrusion, semisolid casting.
  • the formulation of the present invention can be produced by the process available in prior art references.
  • the process available in the prior art references for preparation of sublingual film dosage form are solvent casting, hot- melt extrusion, semisolid casting.
  • Step 3 material casted as film on plain surface and dried to get the film, which was cut in the desired size of the film which will provide the desired dose.
  • step 1 material in extruder having heater, melt the mixture
  • step 2 melt mixture in selected shape dies and allow to cool
  • step 1 The material of step 1 was blended for 15 min in the blender then Lubrication was done by addition of magnesium stearate in the blender.
  • Comparative drug release data of immediate release oral tablet versus sublingual tablet shows faster drug release for sublingual tablet compared to immediate release oral tablet. All the parameters were found satisfactory.
  • Levocetrizine molecule has three ionizable moieties resulting three pKa values, for carboxylic acid moiety Pka 2.19 and for Nitrogen moiety Pka 2.80 and 8.0,
  • the inventors of the present invention have found that by adjusting the pH of the composition in the range of 3 -7 will provide maximum absorption of Levocetirizine.
  • the pH of the saliva is 6. 0; this favours absorption of the drug which remain unionised. Therefore pH range of the Sublingual compositions is important for better absorption of drug through oral mucosa.
  • the present invention provides sublingual composition of Levocetirizine prepared within a pH range of 3-7which provides enhanced absorption of Levocetirizine.
  • Comparative drug release data of immediate release tablet versus sublingual tablet shows faster drug release for sublingual tablet compared to immediate release tablet. All the parameters were found satisfactory.

Abstract

La présente invention concerne une composition pharmaceutique transmucosale stable de lévocétirizine ou d'un sel pharmaceutiquement acceptable de celle-ci et des procédés de préparation de celle-ci. En outre, la présente invention concerne spécifiquement un procédé d'atténuation des symptômes associés des maladies allergiques telles que la rhinite allergique et l'urticaire nécessitant un début d'action rapide.
PCT/IN2021/050190 2020-02-28 2021-02-27 Composition pharmaceutique transmucosale de lévocétirizine WO2021171318A1 (fr)

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CN104224758A (zh) * 2014-09-26 2014-12-24 天津市聚星康华医药科技有限公司 一种盐酸左西替利嗪口腔速溶膜及其制备方法
CN106491566A (zh) * 2016-09-22 2017-03-15 北京万全德众医药生物技术有限公司 一种盐酸左西替利嗪口腔速溶膜及其制备方法

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