阅读说明：本技术 拉莫三嗪悬浮剂剂型 (Lamotrigine suspension formulations ) 是由 K.S.梅塔 D.库玛尔 S.斯里瓦斯塔瓦 A.贾 R.K.辛格 于 2018-02-02 设计创作，主要内容包括：本发明涉及用于拉莫三嗪及其药学上可接受的盐的口服悬浮剂剂型的稳定的即用型粉末,和制备这种组合物的方法。用于拉莫三嗪的口服悬浮剂剂型的液体和粉末以前仅作为临时制剂已知。本发明涉及用于拉莫三嗪的口服悬浮剂剂型的液体和粉末的制备,其具有改进的物理化学性质,从而满足所期望的技术属性。所制备的剂型可用于在吞咽片剂方面有困难的患者,并为医生提供更多的对剂量进行调整的选择性。(The present invention relates to stable ready-to-use powders for oral suspension dosage forms of lamotrigine and pharmaceutically acceptable salts thereof, and to a process for preparing such compositions. Liquids and powders for oral suspension dosage forms of lamotrigine have previously been known only as extemporaneous formulations. The present invention relates to the preparation of liquids and powders for oral suspension dosage forms of lamotrigine having improved physicochemical properties, thereby satisfying the desired technical attributes. The dosage forms prepared are useful for patients who have difficulty swallowing tablets and provide the physician with more options for adjusting the dosage.)

1. an immediate release oral pharmaceutical suspension dosage form of lamotrigine or a pharmaceutically acceptable salt, hydrate or polymorph thereof with one or more pharmaceutically acceptable excipients comprising about 0.1mg/mL to about 100mg/mL of lamotrigine, wherein the pH of the composition is 4-8.

2. the immediate release oral pharmaceutical suspension dosage form of claim 1 comprising from about 0.1mg/mL to about 100mg/mL lamotrigine wherein the composition has a pH of 4-8 and a viscosity of 700-.

3. An immediate release pharmaceutical powder for use in an oral suspension dosage form of lamotrigine or a pharmaceutically acceptable salt, hydrate or polymorph thereof with one or more pharmaceutically acceptable excipients, said suspension dosage form comprising a) about 0.1mg/mL to about 100mg/mL of lamotrigine, b) a pH of 4-8, c) a viscosity of 700-1200cps, d) the composition is free of microbial contaminants for at least 20 days.

4. An immediate release oral pharmaceutical suspension dosage form of lamotrigine or a pharmaceutically acceptable salt, hydrate or polymorph thereof with one or more pharmaceutically acceptable excipients, said suspension dosage form comprising from about 0.01% to about 10% by weight of lamotrigine based on the total weight of the composition, which dosage form exhibits an in vitro dissolution rate of greater than 85% drug release in 20 minutes when placed in a dissolution vessel containing 900ml of 0.1N HCL pH 1.2, maintained at 37 ± 0.5 ℃ and agitated using a USP Type II (paddle) apparatus at a paddle speed of 50 rpm.

5. An immediate release oral pharmaceutical suspension dosage form of lamotrigine or a pharmaceutically acceptable salt, hydrate or polymorph thereof with one or more pharmaceutically acceptable excipients comprising:

a) a thickener selected from gums and/or cellulose;

b) A diluent and/or sweetener selected from sugars and sugar alcohols;

c) A preservative;

d) An antioxidant;

e) a pH adjusting agent in an amount sufficient to maintain the pH of the composition in the range of about 4.0 to about 9.0;

and/or a pharmaceutically acceptable liquid carrier,

wherein the composition is free of glidant.

6. The immediate release oral pharmaceutical suspension dosage form of claims 1, 3, 4 and 5 comprising: about 0.1mg/mL to about 100mg/mL of lamotrigine or a pharmaceutically acceptable salt thereof; about 0.13 to 1.0% xanthan gum; about 40 to 80% sucrose; an effective amount of a pH adjusting agent, a sweetener, and/or a preservative.

7. the immediate release oral pharmaceutical suspension dosage form of claims 1, 3, 4 and 5, wherein the amount of lamotrigine or a pharmaceutically acceptable salt thereof in the suspension ranges from about 0.01% to about 10% by weight based on the total weight of the suspension.

8. An immediate release oral pharmaceutical suspension dosage form of lamotrigine or a pharmaceutically acceptable salt, hydrate or polymorph thereof with one or more pharmaceutically acceptable excipients prepared by a process comprising the steps of:

i. Mixing lamotrigine with one or more pharmaceutically acceptable excipients;

Granulating the mixture of step (i) using a solvent;

(iii) drying the granulated mixture of step (ii);

(iv) milling the mixture of step (iii) to form particles; and

v. mixing the particles of step (iv) optionally with one or more pharmaceutically acceptable excipients to form a suspension powder for reconstitution.

9. an immediate release oral pharmaceutical suspension dosage form of lamotrigine or a pharmaceutically acceptable salt, hydrate or polymorph thereof with one or more pharmaceutically acceptable excipients prepared by a process comprising the steps of:

i. Dissolving/dispersing one or more pharmaceutically acceptable excipients in a portion of water;

Dispersing lamotrigine in the solution of step (i) to form a dispersion;

Mixing the viscosity agent in another portion of water;

(iv) adding the mixture of step (iii) to the dispersion of step (ii);

v. optionally adding one or more pharmaceutically acceptable excipients to the dispersion of step (iv); and

Optionally homogenizing the mixture of step (iv) to form a suspending agent.

10. the immediate release oral pharmaceutical suspension dosage form of the preceding claims comprising a suspension dosage form having a particle size distribution D90 of less than about 200 μm, wherein the composition is prepared using dry granulation, wet granulation, blending, spheronization extrusion, homogenization, and/or hot melt extrusion.

Technical Field

The present invention relates to pharmaceutical compositions in the form of a suspension and a suspension powder for reconstitution comprising lamotrigine. The invention also relates to a process for preparing such a composition.

Background

Anticonvulsants, in particular from the class of phenyl triazines, are widely used clinically as agents for the treatment of epilepsy, bipolar disorders, partial seizures, primary and secondary tonic-clonic seizures, and seizures associated with the Lennox-Gastaut syndrome.

Lamotrigine is the major antiepileptic drug of the phenyltriazine class. It is marketed under the trade name of the united states in the form of tablets, chewable/dispersible tablets, orally disintegrating tablets and sustained release tablets. The commercially available lamotrigine solid dosage forms are indicated for the treatment of epilepsy and bipolar disorder.

However, many patients, particularly elderly and pediatric patients, experience difficulty in swallowing or chewing a tablet dosage form. This has led to the common practice of comminuting tablets to form a powder and combining the powder with Ora-sweet and/or Ora-Plus to prepare a suspension prior to administration. Such temporary formulations raise concerns over such practices as they tend to result in inaccurate dosages and contamination as well as harm to the patient.

There is a continuing need for a drug in liquid or powder form for use in suspension compositions that is suitable for oral administration while maintaining suitable bioavailability of the drug and/or its active metabolites after oral administration. The present invention therefore aims to solve these problems by providing a pharmaceutical composition comprising lamotrigine or a pharmaceutically acceptable salt thereof, which is suitable for oral administration in the form of an oral suspension in liquid or powder form.

lamotrigine is a BCS class II molecule with low solubility and high permeability. Oral administration is associated with a delayed onset of the desired pharmacological effect because lamotrigine is poorly soluble in water, which results in a low dissolution rate of the drug in aqueous media including biological fluids such as gastrointestinal fluids. Formulating lamotrigine into suspension dosage forms is also difficult due to problems with the drug, such as bitterness, and maintaining chemical stability of the drug in suspension dosage forms. Furthermore, the formulated suspension should have the desired technical attributes, such as pourability, viscosity, dissolution, stability, resuspendability and redispersibility, to meet the strict requirements and regulations of health and medical regulatory agencies around the world, especially the USFDA, EMEA, canadian health agency, MHRA and TGA.

after extensive scientific experiments and testing, the present inventors have surprisingly found that it is possible to develop oral suspension dosage forms of lamotrigine with improved physical and chemical properties, which have the desired technical attributes, for use by patients with difficulty swallowing tablets.

objects and summary of the invention

The main object of the present invention is to provide stable pharmaceutical compositions comprising an anticonvulsant drug and one or more pharmaceutically acceptable excipients and/or carriers, and a process for the preparation thereof.

it is another object of the present invention to provide a stable pharmaceutical composition in the form of a suspension comprising lamotrigine or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof together with one or more pharmaceutically acceptable excipients and/or carriers and a process for the preparation thereof.

It is another object of the present invention to provide an oral pharmaceutical composition in the form of a suspension comprising lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixtures thereof together with one or more pharmaceutically acceptable excipients and/or carriers comprising thickeners/viscosity agents, antioxidants, anti-caking agents, anti-foaming agents, pH adjusting agents, colorants, sweeteners, flavourings, solubilizers/wetting agents, buffers, diluents, preservatives and stabilisers.

It is another object of the present invention to develop a suspension comprising lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixtures thereof by a manufacturing process which is consistent and thus feasible for industrial production while maintaining stability and pharmaceutical equivalence to the reference formulation.

the following embodiments further describe the objects of the present invention in terms of the best mode of practice, however, the disclosed invention is not limited to the specific embodiments described below.

According to one embodiment of the present invention there is provided a ready-to-use stable liquid suspension comprising lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixtures thereof and at least one or more pharmaceutically acceptable excipients and/or carriers comprising thickeners/viscosity agents, antioxidants, anti-caking agents, anti-foaming agents, pH adjusting agents, colorants, sweeteners, flavoring agents, solubilizing/wetting agents, buffers, diluents, preservatives and stabilizers.

According to another embodiment of the present invention, there is provided a dry powder for use in a suspension composition suitable for use as a liquid suspension for pediatric or geriatric patients. The composition comprises lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixtures thereof and a pharmaceutically acceptable excipient selected from suspending agents, viscosity enhancing agents, coating agents, preservatives, flavoring agents, thickening/viscosity agents, sweeteners, lubricants, wetting agents, surfactants, buffers and diluents.

According to another embodiment of the present invention, there is provided a method of preparing a stable pharmaceutical composition in the form of a suspension comprising lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixture thereof, wherein lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixture thereof is admixed with a liquid carrier, wherein the liquid carrier comprises an aqueous and/or non-aqueous carrier.

According to another embodiment of the present invention, there is provided a process for the preparation of a stable pharmaceutical composition in the form of a suspension comprising lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixture thereof, wherein lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixture thereof is in micronized form.

according to another embodiment of the present invention, there is provided a process for preparing a stable pharmaceutical composition in the form of a suspension comprising lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixtures thereof, which is coated to mask the bitter taste of the drug.

According to another embodiment of the present invention there is provided a process for the preparation of a ready-to-use liquid suspension of lamotrigine or pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof comprising combining the various components using conventional equipment such as overhead stirrers, ultrasonic instruments, mills, homogenizers operating in the RPM range of about 100-. The components can be added to the mixer in a number of different sequences. Liquid carriers (e.g., aqueous and/or non-aqueous), viscosity agents, sweeteners, taste masking agents, and the like may then be added. The pH of the suspending agent is adjusted to the desired value using an aqueous buffer, as required.

According to another embodiment of the present invention there is provided a process for preparing a dry powder for a suspension composition of lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixtures thereof suitable for suspension in water and/or a suitable water-miscible solvent to form an orally administrable product, which comprises mixing particles of lamotrigine under ambient temperature and humidity conditions with a substantially dry pharmaceutically acceptable excipient selected from suspending agents, viscosity enhancing agents, coating agents, preservatives, flavoring agents, sweetening agents, viscosity agents, lubricants, wetting agents, surfactants, buffers and diluents to form a dry mixture, and transferring the dry mixture to a sealable storage container.

According to another embodiment of the present invention, there is provided a stable pharmaceutical composition in the form of a suspension comprising lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixtures thereof, wherein the composition is substantially free of other polymorphs.

According to another embodiment of the present invention, there is provided a stable pharmaceutical composition in the form of a suspension comprising lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixtures thereof, wherein lamotrigine has a particle size distribution D90 of less than about 200 μm.

According to another embodiment of the present invention, a stable pharmaceutical composition in the form of a suspension comprising lamotrigine or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof in an amount of about 0.01% to about 90% by weight, wherein said composition has the desired technical properties such as pourability, viscosity, dissolution, stability, resuspendability and redispersibility, and a process for preparing the same are provided.

According to another embodiment of the present invention, there is provided a stable pharmaceutical composition in the form of a suspension comprising lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixtures thereof for use in the treatment of epilepsy, bipolar disorder, partial seizures, primary and secondary tonic-clonic seizures and seizures associated with the lun-ga syndrome.

Detailed Description

The present invention may be understood more readily by reading the following detailed description of the invention and by studying the included examples.

As used herein, the term "composition" or "formulation" or "dosage form" (as in a pharmaceutical composition) is intended to encompass a pharmaceutical product comprising an anticonvulsant or an antiepileptic drug, preferably lamotrigine or a pharmaceutically acceptable salt, ester, solvate, polymorph, enantiomer or mixtures thereof, and other inert ingredients (pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with "formulation" and "dosage form". The pharmaceutical compositions of the present invention include, but are not limited to, solutions, powders for suspending agents, oral suspensions, and the like. Preferably, the pharmaceutical composition refers to a suspension. More preferably, the pharmaceutical composition refers to a ready-to-use suspension or a powder for suspension and to a suspension powder for reconstitution, which comprises granules, pellets or beads.

As used herein, the term "ready-to-use suspending agent" refers to a pre-constructed suspending agent that can be administered as such. A "powder for a suspension" or a "dry suspension" requires reconstitution with a liquid carrier to form a suspension.

As used herein, the term "anticonvulsant or antiepileptic or phenyl triazine antiepileptic" is used in a broad sense to include not only "anticonvulsant or antiepileptic or phenyl triazine antiepileptic" per se, but also pharmaceutically acceptable salts, pharmaceutically acceptable esters, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, analogs and various crystalline and amorphous forms thereof, all of which induce the desired pharmacological or physiological effect. Terms such as "active", "active agent", "active" may be used synonymously with "active ingredient".

as used herein, the term "lamotrigine" includes lamotrigine and pharmaceutically acceptable salts, esters, hydrates, solvates, polymorphs, enantiomers, prodrugs, chelates, derivatives, analogs, complexes or mixtures thereof. The pharmaceutical modified release liquid composition of the present invention comprises lamotrigine in an amount of about 0.01% w/w to about 50% w/w of the total composition, in particular about 0.01% to about 10% w/w of the total composition.

The term "excipient" refers to pharmacologically inactive ingredients such as thickeners, viscosity agents, anti-caking agents, anti-foaming agents, pH adjusting agents, antioxidants, sweeteners, flavoring agents, solubilizing/wetting agents, buffers, preservatives and the like. Excipients used in the preparation of liquid pharmaceutical compositions are safe and non-toxic. When an excipient is mentioned, it includes one and more than one of said excipients. Co-processed excipients are also included within the scope of the present invention. Further, the excipient may be in the form of a powder or a dispersion. Combinations of excipients having the same function may also be used to achieve the desired formulation characteristics. In addition to the above components, the lamotrigine oral suspension dosage forms may optionally contain other Excipients commonly found in Pharmaceutical compositions, such as other solvents, taste masking agents, antioxidants, bulking agents, acidifying agents, enzyme inhibitors and other components described in Handbook of Pharmaceutical Excipients, Rowe et al, eds.,6th Edition, Pharmaceutical Press (2009).

As used herein, "substantially free" refers to a pharmaceutical composition of lamotrigine that does not convert to other polymorphic forms during formulation development or stability studies.

As used herein, the term "about" means ± about 20% of the stated value, thus "about 10%" means about 08% to 12%.

As used in this specification, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, when reference is made to a "method," it includes one or more methods, and/or one or more steps of the types of methods described herein, and/or those that will be apparent to one of skill in the art upon reading this disclosure.

The term "stable" as used herein refers to chemical stability wherein the total related substances formed after storage at 40 ℃ and 75% relative humidity (r.h.) or 25 ℃ and 60% r.h. for a period of at least one month, in particular for a period of two months, more in particular for a period of at least three months, do not exceed 5% w/w.

unless otherwise indicated, the weight percentages expressed herein are based on the final weight of the composition or formulation.

The present invention is a stable pharmaceutical composition relating to a ready-to-use oral liquid suspension or to a dry powder for a suspension composition suitable for administration in the form of a liquid suspension to a subject in need thereof, comprising lamotrigine or a pharmaceutically acceptable salt thereof. The suspension dosage form is capable of masking the taste of the drug and also provides the drug in a form suitable for dissolution, thereby achieving patient compliance, particularly for children and the elderly.

According to one embodiment of the present invention, stable pharmaceutical compositions in the form of suspensions comprising lamotrigine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients and/or liquid carriers and processes for their preparation are provided.

another embodiment of the present invention relates to an immediate release oral pharmaceutical suspension dosage form of lamotrigine or a pharmaceutically acceptable salt, hydrate or polymorph thereof with one or more pharmaceutically acceptable excipients comprising:

a) a viscosity/thickening agent selected from gums and/or cellulose;

b) A diluent and/or sweetener selected from sugars and sugar alcohols;

c) a preservative;

d) An antioxidant;

e) A pH adjusting agent in an amount sufficient to maintain the pH of the composition in the range of about 4.0 to about 9.0;

And/or a pharmaceutically acceptable liquid carrier,

Wherein the composition is free of glidant.

According to another embodiment of the present invention there is provided a stable suspension formulation comprising lamotrigine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients and/or liquid carriers, wherein the viscosity agent is selected from the group consisting of gums, such as xanthan gum, acacia gum, locust bean gum, cellulose, mixtures of carboxymethylcellulose and microcrystalline cellulose, polyvinyl alcohol and polyvinyl pyrrolidone, colloidal silicon dioxide, carbomers and combinations thereof.

according to an aspect of an embodiment of the present invention there is provided a stable suspension comprising lamotrigine or a pharmaceutically acceptable salt thereof wherein the viscosity agent is xanthan gum in combination with a mixture of carboxymethylcellulose and microcrystalline cellulose.

According to another aspect of embodiments of the present invention there is provided a stable suspension comprising lamotrigine or a pharmaceutically acceptable salt thereof wherein the ratio of xanthan gum to the mixture of carboxymethylcellulose and microcrystalline cellulose is from 3:1 to 1:3 w/w.

according to another aspect of embodiments of the present invention there is provided a stable suspension formulation comprising lamotrigine or a pharmaceutically acceptable salt thereof, wherein the viscosity agent is a mixture of carrageenan, carboxymethylcellulose and microcrystalline cellulose, and combinations thereof.

According to another aspect of an embodiment of the present invention there is provided a stable suspension comprising lamotrigine or a pharmaceutically acceptable salt thereof wherein the viscosity agent is a combination of carrageenan, xanthan gum and a mixture of carboxymethylcellulose and microcrystalline cellulose.

According to another embodiment of the present invention, there is provided a stable pharmaceutical composition in the form of a suspension comprising lamotrigine or a pharmaceutically acceptable salt thereof and/or a liquid carrier, wherein the diluent is selected from the group consisting of sucrose, sugar alcohols, sorbitol, xylitol, erythritol, starch, pregelatinized starch, calcium carbonate, anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, calcium sulfate, powdered cellulose, silicified microcrystalline cellulose and combinations thereof.

in one aspect of an embodiment of the invention, the sucrose has a particle size such that not less than 90% of the particles are less than 200 μm. In particular, sucrose has a particle size of not less than 90% of the particles smaller than 100. mu.m. This helps to achieve improved homogeneity of the drug in the mixture.

According to one embodiment of the present invention, there is provided a stable pharmaceutical composition in the form of a suspension comprising lamotrigine or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable excipients and/or a liquid carrier, wherein the liquid carrier is selected from aqueous and non-aqueous carriers and optionally with one or more pharmaceutically acceptable excipients. The aqueous carrier is selected from water or a combination of water and a water-miscible organic solvent. The non-aqueous carrier is selected from oils, e.g., peanut oil, soybean oil, corn oil, sesame oil, cottonseed oil; mineral oil; a fatty acid ester; mono-or di-fatty acid esters of polyethylene glycol; glycerol monooleate; ethyl oleate; acetylated glycerides; or a combination thereof.

According to another embodiment of the present invention, there is provided a stable pharmaceutical composition in the form of a suspension comprising lamotrigine or a pharmaceutically acceptable salt thereof and/or a liquid carrier, wherein the sweetener is selected from the group consisting of sugars or sugar alcohols, such as sucrose, dextrose, sucralose, sorbitol, fructose, mannitol and invert sugar and sugar substitutes, such as saccharin sodium, aspartame and combinations thereof.

According to another embodiment of the present invention, there is provided a stable pharmaceutical composition in the form of a suspension comprising lamotrigine or a pharmaceutically acceptable salt thereof and/or a liquid carrier, wherein the preservative is selected from benzoic acid and salts thereof, sorbic acid and salts thereof, parabens, sodium metabisulfite, chlorhexidine, sodium citrate, Butylhydroxytoluene (BHT), Butylhydroxyanisole (BHA), tocopherol, ethylenediaminetetraacetic acid, propyl gallate and quaternary ammonium compounds.

according to another embodiment of the present invention, there is provided a stable pharmaceutical composition in the form of a suspension formulation comprising lamotrigine or a pharmaceutically acceptable salt thereof and/or a liquid carrier, wherein the antioxidant is selected from ascorbic acid, tert-butylhydroquinone, sodium metabisulphite, glutathione, sodium bisulphite, sodium sulphite, alpha-tocopherol, alpha-tocopheryl acetate, monothioglycerol, cysteine, ascorbyl palmitate, acetyl cysteine, dithiothreitol, sodium metabisulphite, thiourea and sodium thiosulphate.

according to other embodiments of the present invention, there is provided a stable suspending agent comprising about 0.01% to about 90% by weight of lamotrigine or pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof, based on the total weight of the composition, preferably in the range of about 0.1% to about 40% by weight.

According to other embodiments of the present invention, there is provided a stable suspension comprising lamotrigine or a pharmaceutically acceptable salt thereof, wherein the amount of lamotrigine in the suspension ranges from about 0.1mg/mL to about 400 mg/mL. The amount of lamotrigine in the suspension preferably ranges from about 0.5mg/mL to 300mg/mL, preferably from about 0.5mg/mL to 200mg/mL, preferably from about 0.5mg/mL to 100 mg/mL. More preferably, the amount of lamotrigine in the suspension is in the range of about 0.5mg/mL to 75 mg/mL.

According to an aspect of an embodiment of the present invention there is provided a stable suspension comprising lamotrigine or a pharmaceutically acceptable salt thereof, wherein the amount of lamotrigine in the suspension is 1mg/mL, 2mg/5mL, 5mg/5mL, 25mg/5mL, 50mg/5mL and 100mg/5 mL.

according to other embodiments of the present invention, there is provided a stable suspending agent comprising lamotrigine or a pharmaceutically acceptable salt thereof, wherein the pH of the suspending agent ranges from about 3 to 8. Preferably, the pH range is about 4-7.

According to other embodiments of the present invention, there is provided a stable suspension comprising lamotrigine or a pharmaceutically acceptable salt thereof, wherein said suspension is a liquid suspension packaged in a bottle.

According to another embodiment of the present invention, there is provided a stable suspension comprising lamotrigine or a pharmaceutically acceptable salt thereof, wherein said suspension is a powder for suspension packaged in a bottle or capsule.

According to another embodiment of the invention, lamotrigine has a particle size distribution D90 of less than about 200 μm. Lamotrigine has a particle size distribution D90 of between 5 μm and 200 μm. Lamotrigine has a particle size distribution in particular with a D90 of between 5 μm and 175 μm, in particular with a D90 of between 5 μm and 150 μm, in particular with a D90 of between 5 μm and 125 μm, in particular with a D90 of between 5 μm and 100 μm and in particular with a D90 of between 5 μm and 75 μm.

According to one embodiment of the invention, there is provided a stable suspension comprising lamotrigine or a pharmaceutically acceptable salt thereof, wherein the composition has an equivalent (compatible) dissolution compared to a commercially available chewable dispersible tablet of lamotrigine (tablet).

according to one embodiment of the present invention, there is provided a process for the preparation of a stable suspension formulation comprising lamotrigine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients and/or liquid carriers.

according to one embodiment of the present invention, there is provided a process for the preparation of a stable suspension formulation comprising lamotrigine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients and/or liquid carriers, wherein the processes used are blending, dry granulation, wet granulation, spheronization extrusion, homogenization and the like.

According to another embodiment of the present invention, there is provided a suspension comprising lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixtures thereof, wherein lamotrigine is used in amorphous form prepared by hot melt extrusion.

According to one embodiment of the present invention, there is provided a process for the preparation of a ready-to-use suspension comprising lamotrigine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients and/or liquid carriers, wherein the process comprises the steps of:

(i) Dissolving/dispersing one or more pharmaceutically acceptable excipients in a portion of water;

(ii) (ii) dispersing lamotrigine in the solution of step (i) to form a dispersion;

(iii) Mixing the viscosity agent in another portion of water;

(iv) (iv) adding the mixture of step (iii) to the dispersion of step (ii); and

(v) (iii) optionally adding one or more pharmaceutically acceptable excipients to the dispersion of step (iv); and

(vi) (iv) optionally homogenizing the mixture of step (iv) to form a suspending agent.

According to a further embodiment of the present invention, there is provided a process for the preparation of a powder for suspension comprising lamotrigine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients and/or liquid carriers, said process comprising the steps of:

(i) mixing lamotrigine with one or more pharmaceutically acceptable excipients;

(ii) (ii) granulating the mixture of step (i) using a solvent;

(iii) (iii) drying the granulated mixture of step (ii);

(iv) (iv) milling the mixture of step (iii) to form particles; and

(v) (iii) mixing the particles of step (iv) optionally with one or more pharmaceutically acceptable excipients to form a suspension powder for reconstitution.

According to a further embodiment of the present invention, there is provided a process for the preparation of a powder for suspension comprising lamotrigine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients and/or liquid carriers, wherein the process comprises the steps of:

(i) Mixing lamotrigine with one or more pharmaceutically acceptable excipients;

(ii) (ii) compressing the mixture of step (i) to form a pre-compressed tablet (slug);

(iii) (iii) grinding the pre-tablet of step (ii) to form granules; and

(v) (iv) mixing the granules of step (iii) optionally with one or more pharmaceutically acceptable excipients to form a suspension powder for reconstitution.

According to a further embodiment of the present invention, there is provided a process for the preparation of a powder for suspension comprising lamotrigine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients and/or liquid carriers, wherein the process comprises the steps of:

(i) Mixing lamotrigine with one or more pharmaceutically acceptable excipients; and

(ii) (ii) optionally, lubricating the mixture of step (i) to form a suspension powder for reconstitution.

The powder/granules for oral suspension may be reconstituted with water or the powder/granules for oral suspension may be administered by sprinkling the powder/granules onto a teaspoon of apple sauce or pouring the granules into a cup or teaspoon containing a teaspoon of apple juice.

The suspending agent of the present invention provides advantages such as no caking when the composition is shaken even after long-term storage, and good pourability. The suspending agents of the present invention have good physical stability, e.g. low sedimentation levels (reduced or no caking) and are easily redispersible upon stirring. Moreover, it provides dose uniformity during each administration.

According to another embodiment of the present invention, there is provided a ready-to-use liquid suspension comprising lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixtures thereof, and at least one or more pharmaceutically acceptable excipients and/or liquid carriers comprising thickening/viscosity agents, antioxidants, anti-caking agents, antifoaming agents, pH adjusting agents, sweeteners, flavoring agents, solubilizing/wetting agents, buffers and preservatives, wherein said suspension is readily dispersible or re-suspendable in a pharmaceutically acceptable liquid carrier comprising aqueous and/or non-aqueous carriers.

According to another embodiment of the present invention, there is provided a stable suspension comprising lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixtures thereof, wherein the composition is substantially free of other polymorphs.

According to another embodiment of the present invention, there is provided a suspension formulation comprising from about 0.01% to about 90% by weight of lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixtures thereof, wherein said composition exhibits desired technical attributes such as pourability, viscosity, dissolution, stability, resuspendability and redispersibility.

In another embodiment, the liquid composition of the invention comprises lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixtures thereof, having a particle size distribution of D90 of less than about 200 μm, D50 of less than about 100 μm and D10 of less than about 50 μm. In particular, D50 is about 5 μm to about 100. mu.m. The particle size of lamotrigine can be measured by suitable techniques such as laser Light Scattering (e.g., Malvern Light Scattering), Coulter counter, microscopy, Fraunhofer diffraction and any other technique known in the art. This particle size can be obtained by a final step during the manufacture of lamotrigine or by using conventional micronization techniques after the crystallization operation.

In another embodiment of the present invention is provided a powder for use in a suspension composition comprising more than 0.01% by weight based on the total weight of the composition of lamotrigine or a pharmaceutically acceptable ester, salt, solvate, polymorph, enantiomer or mixtures thereof, together with one or more pharmaceutically acceptable excipients and/or liquid carriers such as thickeners/viscosity agents, antioxidants, anti-caking agents, anti-foaming agents, pH adjusting agents, sweeteners, flavoring agents, solubilizing/wetting agents, buffers and preservatives, aqueous or non-aqueous carriers and the like.

The carrier/vehicle/solvent used in the suspension of the invention includes aqueous and non-aqueous carriers including, but not limited to, water, alcohols, polyethylene glycol, propylene glycol or glycerol buffers, oils, or combinations thereof. The oil comprises peanut oil, soybean oil, corn oil, sesame oil, cottonseed oil, acetylated glyceride, ethyl oleate, mineral oil, fatty acid ester, and mono-or di-fatty acid ester of polyethylene glycol or glyceryl monooleate. In particular, the suspending agent is aqueous based. By "aqueous carrier" is meant a suspension comprising water, or a combination of one or more organic solvents that are miscible with water. Water miscible solvents include, but are not limited to, propylene glycol, polyethylene glycol, and ethanol. By "non-aqueous carrier" is meant a suspension wherein the carrier does not contain water. The carrier may also include one or more pharmaceutically acceptable excipients, which may be in dissolved or dispersed form. The carrier is present in an amount of about 30 to about 95 w/w%, particularly about 50 to about 95 w/w%.

A variety of useful viscosity/thickening agents include, but are not limited to, gums such as xanthan gum, carrageenan, gum arabic, guar gum, locust bean gum, tragacanth gum; cellulose such as hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, a mixture of microcrystalline cellulose and carboxymethyl cellulose (RC); polyvinylpyrrolidone; alginic acid; an alginate; sodium alginate; bentonite; carbomers (carboxyvinyl polymers) such as those available under the trade name carbopol; cetostearyl alcohol; maltodextrin; polyvinyl alcohol; colloidal silica, propylene carbonate; propylene glycol; sodium starch glycolate; starch; acrylic polymers, and the like. The viscosity agent is present in an amount of about 0.05% to about 20% w/w of the composition. In particular, the viscosity agent is present in an amount of about 0.1% to about 10% w/w of the composition. More particularly, the viscosity agent is present in an amount of about 0.1% to about 5% w/w of the composition. More specifically, the viscosity agent is present in an amount of about 0.1% to about 3% w/w of the composition.

The suspension is readily pourable and has a viscosity of 100 to 5000cP at 25 ℃ when shaken. In particular, the viscosity is in the range of 100 to 2500cP at 25 ℃. More particularly, the viscosity is in the range of 100 to 1500cP at 25 ℃.

The term "shaking" as used herein refers to shaking prior to use, e.g., by the patient, e.g., vigorous shaking, e.g., by hand, e.g., for 5 to 40 seconds.

Viscosity can be measured at room temperature (25 ℃) using a suitable instrument such as a Brookfield viscometer, Haake VT 550 viscometer.

diluents or fillers are substances that generally provide volume to the composition. Various useful fillers or diluents include, but are not limited to, sucrose, sugar alcohols, sorbitol, xylitol, erythritol, starch, pregelatinized starch, calcium carbonate, anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, calcium phosphate, calcium sulfate, powdered cellulose, silicified microcrystalline cellulose, cellulose acetate, lactose, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polydextrose, sodium alginate, sodium chloride, and or mixtures thereof. The preferred diluent used is sucrose. The diluent is present in an amount of 5 to 80% of the total composition.

Surfactants or wetting agents or defoamers improve the wetting and/or enhance the dissolution of the dosage form. These agents also help prevent foam formation during high shear agitation and other manufacturing processes. Few active ingredients are fluffy in nature and do not suspend properly. These types of active ingredients typically float on the surface of the vehicle/solvent used in the suspension. Surfactants or wetting agents or defoamers contemplated for use in the present invention include, but are not limited to, anionic surfactants, cationic surfactants, amphoteric surfactants, nonionic surfactants, and macromolecular surfactants. For example, polyethylene glycol stearate, poloxamers, polysorbates, sodium lauryl sulfate, dimethicone, simethicone, and simethicone, among others.

Various useful preservatives include, but are not limited to, parabens, such as methyl paraben, propyl paraben, butyl paraben and salts thereof, sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, methyl paraben, ethyl paraben, sodium metabisulfite, chlorhexidine, diazacyclodinyl urea (diazolidinyl urea), sodium citrate, Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), tocopherol, ethylenediaminetetraacetic acid, propyl gallate, quaternary ammonium compounds, such as benzalkonium chloride and cetyl pyridinium chloride, phenyl ethanol, and the like. In particular, the preservative is selected from benzoic acid and its salts and parabens. The preservative is present in an amount of about 0.001% w/w to about 3% w/w.

Anti-caking agents help to resuspend the ingredients suspended in the formulation. Typically, suspension formulations contain micronized particles of the active ingredient and inactive ingredient which settle at the bottom of the container and form a thin hard cake which is not easily re-suspended after shaking. Anti-caking agents help to improve the resuspendability of the formulation. A variety of useful anti-caking agents include, but are not limited to, colloidal silica and/or colloidal silica, calcium phosphate, magnesium oxide, magnesium silicate, calcium silicate, and the like.

a variety of useful antioxidants include, but are not limited to, ascorbic acid, tert-butylhydroquinone, sodium metabisulfite, glutathione, sodium bisulfite, sodium sulfite, alpha-tocopherol, alpha-tocopheryl acetate, monothioglycerol, cysteine, ascorbyl palmitate, acetyl cysteine, dithiothreitol, sodium metabisulfite, thiourea, sodium thiosulfate, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), and propyl gallate.

Various useful sweeteners include, but are not limited to, sugars or sugar alcohols such as sucrose, dextrose, sucralose, sorbitol, fructose, mannitol, and invert sugar, and sugar substitutes such as sodium saccharin, aspartame. Sugars or sugar alcohols may also be used as fillers. The sweetener preferably used is saccharin sodium.

Various useful flavoring agents, including but not limited to, spices such as bananas, lemons, oranges, grapes, limes and grapefruits, herbs and fruit essences including apples, bananas, pears, peaches, strawberries, raspberries, cherries, plums, pineapples, apricots; synthetic flavor oils and flavoring aromatics and/or natural oils; extracts of plant leaves, flowers, and fruits such as cinnamon oil, oil of wintergreen, peppermint oil, clove oil, citrus oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, bitter almond oil, and cinnamon oil; maltol, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid, and combinations thereof.

a variety of useful isotonic agents include, but are not limited to, sodium chloride, mannitol, D-sorbitol, glucose, glycerol and the like.

Various useful pH adjusting agents or buffers include, but are not limited to, citrate buffers, phosphate buffers, or any other suitable buffer known in the art, including monobasic sodium phosphate (monobasic), gluconic acid, lactic acid, citric acid, acetic acid, sodium gluconate, sodium lactate, sodium citrate, sodium acetate, potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate.

Various useful taste masking agents include, but are not limited to, water-soluble and/or insoluble polymeric excipients, water-insoluble non-polymeric excipients, adsorbents, ion exchange resins, carbomers, alkali or alkaline earth chlorides or derivatives thereof.

The pharmaceutical compositions of the present invention may be packaged in suitable packages/containers, such as amber polyethylene terephthalate (PET) bottles, glass bottles, High Density Polyethylene (HDPE) bottles, Low Density Polyethylene (LDPE) bottles, polypropylene (PP) bottles, sachets, and the like. Glass or plastic bottles are equipped with child proof closures (child proof). The package may include a syringe (labeled in mL) to facilitate administration.

Containers, such as bottles, having a fill volume of, for example, about 50mL to about 500mL, contain lamotrigine suspension. The selected package is made of a material that is non-reactive with the suspending agent and the suspended powder for reconstitution. Containers for storing oral suspensions may be used to administer multiple doses of lamotrigine.

The liquid pharmaceutical compositions of the present invention are useful for the treatment of epilepsy, bipolar disorder, partial seizures, primary and secondary tonic-clonic seizures, and seizures associated with the lun-ga syndrome.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art in view of the disclosure of the specification. The invention is further defined by reference to the following examples describing in detail the methods of making and testing lamotrigine pharmaceutical compositions. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. The following examples are intended to illustrate the invention without limiting its scope.

Examples

TABLE 1 Ready-to-use suspension concentrates

the operation is as follows:

1. sucrose and sorbitol were added to hot water to form a solution.

2. lamotrigine was dispersed in the solution of step 1.

3. Xanthan gum and Avicel RC 591 were mixed in another portion of water and added to the dispersion of step 2.

4. Sodium saccharin, dibasic monosodium phosphate, potassium sorbate and/or sodium benzoate, methyl paraben, propyl paraben and the desired fragrance are added to the dispersion of step 3 with stirring.

5. the dispersion of step 4 was homogenized and the volume was made up with the remaining amount of water to form a suspension.

TABLE 2 powders for suspending agent

the operation is as follows:

1. mixing lamotrigine, sucrose, anhydrous dibasic sodium phosphate and sorbitol powder.

2. Sodium saccharin was dissolved in water.

3. The mixture of step 1 was granulated with the solution of step 2.

4. the wet mass of step 3 is dried and milled to form granules.

5. Avicel RC 591, xanthan gum, desired flavor were mixed and blended with the granules of step 4 to form a suspension powder for reconstitution.

The suspension powder for reconstitution was reconstituted with water to provide a concentration of 10 mg/mL.

As is commonly known to those skilled in the art, reference is made to USP, Remington: the Science and Practice of Pharmacy 20th Edition and L.Lachman, H.A.Lieberman, J.L.Kanig (1986) performed The following tests.

Testing of lamotrigine

The ready-to-use suspension of example 2 and the powder for suspension of example 4 were analyzed by HPLC for drug content according to the method disclosed in USP <621>, and the results are listed in Table 3.

TABLE 3 testing of lamotrigine

Composition comprising a metal oxide and a metal oxide	% test
		Example 2	100.1
Example 4	106.0

pH data: potentiometric determination of pH Using USP <791>

The pH of the reconstituted suspension of example 4 was determined to be 5.6.