Dosage forms of trofinetide and its pharmaceutically acceptable salt thereof

Abstract

The present invention relates to a stable powder composition for an oral solution or suspension (PFOS) comprising of trofinetide and atleast one or more pharmaceutically acceptable excipients, and process for the preparation thereof. The present invention relates to a stable ready-to-use oral solution comprising of trofinetide and atleast one or more pharmaceutically acceptable excipients, and process for the preparation thereof. The present invention relates to stable dosage forms comprising of trofinetide and atleast one or more pharmaceutically acceptable excipients which is useful in treating a variety of neurodegenerative disorders, autism spectrum disorders, and neurodevelopmental disorders.

Description

[0001] DOSAGE FORMS OF TROFINETIDE AND ITS PHARMACEUTICALLY

[0002] ACCEPTABLE SALT THEREOF

[0003] FIELD OF INVENTION

[0004] The present invention relates to a stable powder composition for an oral solution or suspension (PFOS) comprising of trofinetide and atleast one or more pharmaceutically acceptable excipients, and process for the preparation thereof.

[0005] The present invention relates to a stable ready-to-use oral solution comprising of trofinetide and atleast one or more pharmaceutically acceptable excipients, and process for the preparation thereof.

[0006] The present invention relates to stable dosage forms comprising of trofinetide and atleast one or more pharmaceutically acceptable excipients which is useful in treating a variety of neurodegenerative disorders, autism spectrum disorders, and neurodevelopmental disorders.

[0007] BACKGROUND OF THE INVENTION

[0008] Autism spectrum disorders (ASD) are a collection of linked developmental disorders, characterized by abnormalities in social interaction and communication, restricted interests and repetitive behaviours. Current classification of ASD recognises five distinct forms: classical autism or Autistic Disorder, Asperger syndrome, Rett syndrome, childhood disintegrative disorder and pervasive developmental disorder not otherwise specified (PDD- NOS). A sixth syndrome, pathological demand avoidance (PDA), is a further specific pervasive developmental disorder.

[0009] Trofinetide is a weak CYP3A4 inhibitor. Trofinetide is chemically known as (2S)-2-{[(2S)- l-(2-aminoacetyl)-2-methylpyrrolidine-2carbonyl]amino}pentanedioic acid with a molecular weight of 315.33 g / mol. EP 0366638 discloses GPE (a tri-peptide consisting of the amino acids Gly-Pro-Glu) and its di-peptide derivatives Gly-Pro and Pro-Glu and discloses that GPE is effective as a neuromodulator and is able to affect the electrical properties of neurons.

[0010] US7041314 covers Formula I or a pharmaceutically acceptable salt thereof.

[0011] US9212204 covers synthetic analogs and peptidomimetics of glycyl-L-prolyl-L-glutamic acid (GPE). It discloses a method for treating a human being suffering from a symptom of Rett Syndrome, comprising oral administration to said human being an effective amount of an aqueous solution of Glycyl-2-Methyl-L-prolyl-L-glutamate (G-2-MePE). The compounds according to invention can be administered as pharmaceutical compositions by one of the following routes: oral, topical, systemic (e.g. transdermal, intranasal, or by suppository), or parenteral (e.g. intramuscular, subcutaneous, or intravenous injection or by intraspinal or intercistemal injection or by implantation, and by infusion through such devices as osmotic pumps, implantable pumps, transdermal patches, and the like. Compositions can take the form of tablets, pills, capsules, semisolids, powders.

[0012] According to DAYBUE® USA label DAYBUE is a pink to red, oral solution with each 5 mb containing 1 g of trofmetide (200 mg / mL). The oral solution also contains FD&C Red No. 40, maltitol, methylparaben sodium, propylparaben sodium, purified water, strawberry flavor, and sucralose as inactive ingredients.

[0013] Currently, DAYBUE oral solution is available in a 500ml multi -dose HDPE bottles from which the patients are required to take desired volumes like 25ml, 30ml, 40ml, 50ml, 60ml twice daily. In these multi -dose packs sometimes there are chances of dosing errors because of wrong dose measurements. Thus, there is a need to develop new dosage forms of Trofmetide which is simple, easy to pick or administer to needed patients. There is a need to develop a solid drug product which is advantageous as compared to oral solution and exhibits acceptable physical and chemical stability throughout the product shelf-life when stored in its storage conditions. SUMMARY OF THE INVENTION

[0014] In present disclosure it provides a stable powder composition for an oral solution or suspension comprising of trofmetide and atleast one or more pharmaceutically acceptable excipients.

[0015] In present disclosure it provides a stable powder composition for an oral solution or suspension comprising of trofmetide and atleast one or more pharmaceutically acceptable excipients, wherein the powder composition is devoid of antimicrobial preservatives.

[0016] In present disclosure it provides a process for the preparation of a stable powder composition for an oral solution or suspension comprising of trofmetide and atleast one or more pharmaceutically acceptable excipients.

[0017] In present disclosure it provides a stable powder composition for an oral solution or suspension comprising of trofmetide, which is useful in treating a variety of neurodegenerative disorders, autism spectrum disorders, and neurodevelopmental disorders.

[0018] In present disclosure it provides a stable powder composition for an oral solution or suspension comprising of trofmetide, which is useful for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older.

[0019] In present disclosure it provides a stable ready-to-use oral solution comprising of trofmetide and atleast one or more pharmaceutically acceptable excipients and process of making the same.

[0020] In present disclosure it provides a stable ready-to-use oral solution comprising of trofmetide and atleast one or more pharmaceutically acceptable excipients, wherein the powder composition is devoid of antimicrobial preservatives, and process of making the same.

[0021] In present disclosure it provides a stable ready-to-use oral solution comprising of trofmetide and atleast one or more pharmaceutically acceptable excipients, which is useful in treating a variety of neurodegenerative disorders, autism spectrum disorders, and neurodevelopmental disorders.

[0022] In present disclosure it provides a stable ready-to-use oral solution of trofinetide which is useful for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older.

[0023] DETAILED DESCRIPTION OF THE INVENTION

[0024] The information that follows illustrates various embodiments of the compositions disclosed herein. For the avoidance of doubt, it is specifically intended that any particular feature(s) described individually in any one of these paragraphs (or part thereof) may be combined with one or more other features described in one or more of the remaining paragraphs (or part thereof). In other words, it is explicitly intended that the features described below individually in each paragraph (or part thereof) represent important aspects of the invention that may be taken in isolation and also combined with other important aspects of the invention described elsewhere within this specification as a whole and including the examples and figures. The skilled person will appreciate that the compositions claimed herein extends to such combinations of features and that these have not been recited in detail here in the interests of brevity.

[0025] Definitions of some of the terms used herein are detailed below:

[0026] The use of the terms “a” and “an” and “the” and similar references in the context of describing the composition described herein (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0027] The term “about” as used herein embodies standard error associated with a physico-chemical observable. As used herein, the term “about” means a slight variation of the value specified, for example, within 10% of the value specified. A stated amount for a compositional ingredient that is not preceded by the term “about” does not mean that there is no variance for the stated term, as one of ordinary skill would understand that there may be the possibility of a degree of variability generally associated with experimental error.

[0028] The term “therapeutically effective amount” or effective dose” as used herein refers to the amount or dose of Trofmetide that is sufficient to initiate therapeutic response in a patient.

[0029] The term “treating”, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, unless otherwise indicated, refers to the act of “treating” as defined immediately above.

[0030] The term "stable" as used herein refers to physical stability or chemical stability of a “PFOS” or a “ready-to-use” dosage forms comprising Trofmetide or pharmaceutically acceptable salts and at least one or more pharmaceutically acceptable excipients. Stability over time may be evaluated based on pre-defined criteria including assay of active and related compounds, appearance, color, and pH. Physical stability refers to consistent physical properties of composition throughout the product shelf-life. For e.g. Appearance, description, flow properties and others. Chemical stability refers to consistency in obtaining acceptable results of drug assay, drug content uniformity and drug impurities or related substances.

[0031] The term "therapeutically effective amount" means the amount that, when administered to an animal for treating a disease, is sufficient to effect treatment forthat disease.

[0032] The term "excipient" means a pharmacologically inactive component such as flavor enhancers, flavoring agents, Sweeteners, chelating agent, fillers, diluents, glidants, viscosity enhancing agent, anti-oxidants, and combinations thereof which is free of preservative may also be utilized.

[0033] The term "antioxidant" is intended to mean an agent that inhibits oxidation and thus is used to prevent the deterioration of preparations by the oxidative process . These antioxidants help extend the shelf life of pharmaceutical suspensions by inhibiting the harmful effects of oxidation, ensuring the maintenance of product quality and efficacy overtime. The term “preservative” means which prevents the unwanted growth of bacteria, fungi or yeast, in the formulation.

[0034] The term “viscosity enhancing agent or thickening agent or suspending agent” are interchangeable to each other and are used to reduces its surface tension, thereby increasing its spreading and wetting properties of dispersed or suspended particles.

[0035] The term “sweetener or sweetening agent” means which makes the suspension palatable and more pleasing to the patient and to mask the taste sweetening agent are added to the formulation.

[0036] The term “chelating agent” means chemical compounds that react with metal ions to form a stable, water-soluble complex.

[0037] The term “flavoring agent or flavor” means which adds flavour to the drug product.

[0038] The term “Glidants” are substances that improve flowability of a powder.

[0039] The term “Trofmetide” API may exist either in crystalline or amorphous or a mixture of both.

[0040] A first embodiment relates to a powder composition for an oral solution or suspension comprising: a) Trofmetide or salts; b) atleast one or more pharmaceutically acceptable excipients; wherein the composition is free of preservative.

[0041] In one aspect of the first embodiment, it relates to a stable powder composition for an oral solution or suspension comprising trofmetide and atleast one or more pharmaceutically acceptable excipients, wherein the powder composition is devoid of preservatives. Preferably, the trofmetide powder composition is devoid of parabens. The pharmaceutical excipients are selected from diluents, sweeteners, flavors, dyes, glidants, antioxidants and combinations thereof. In one aspect of the first embodiment, the diluents are selected from mannitol, maltitol, isomalt, sorbitol, lactose, starch, hydrolyzed starch, maltodextrin, sucrose, dextrose, or combinations thereof.

[0042] In one aspect of the first embodiment, glidant are selected from but not limited to calcium silicate, magnesium silicate, colloidal silicon dioxide, talc and the like, or mixtures thereof.

[0043] In one aspect of the first embodiment, the sweeteners are selected from acesulfame potassium, isomalt, Magna Sweet, maltitol, mannitol, sorbitol, sucralose, xylitol, alitmae, neohesperidin dihydrochalcone, trehalose, tagatose, neotame, saccharin and salts thereof, stevioside, erythritol, isomaltulose, polydextrose, cyclamate, osladine, sucrose, fructose, or glucose, or combinations thereof.

[0044] In one aspect of the first embodiment, the flavors are selected from cherry, grape, orange, pink lemonade, raspberry, grape, lemon, orange, strawberry, tutti-frutti, tangerine, apple, watermelon, pineapple, banana, peach, kiwi, mango, mixed berry, raspberry lemonade, wild blackberry, blue raspberry, citrus, blueberry, lime, lemon lime, grapefruit, pomegranate, pear, or plum flavors, or combinations thereof.

[0045] In one aspect of the first embodiment, the dyes are selected from riboflavin, cochineal dye, carmine, blue No. 1 for food use, yellow No. 4 aluminum lake for food use, yellow No. 5 aluminum lake for food use, red No. 3 aluminum lake for food use, red No. 106 for food use, iron sesquioxide, yellow iron sesquioxide, pharmaceutical dyes such as FD&C Blue No. 2, FD&C Blue No. 1, FD&C Green No. 3, FD&C Red No. 3, FD&C Red No. 4, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Yellow No. 5, or combinations thereof.

[0046] In one aspect of the first embodiment, the antioxidants are selected from alpha-lipoic acid, ascorbic acid (including L-ascorbic acid, also called vitamin C), fatty acid esters of ascorbic acid such as ascorbyl palmitate and ascorbyl stearate, and salts of ascorbic acid such as sodium, calcium, and potassium ascorbate, Potassium citrate, Tartaric acid and Non-acidic antioxidants can also be used in the dosage forms. Nonlimiting examples of non-acidic antioxidants include vitamin A (including beta-carotene and retinol), vitamin E (including alpha-tocopherol), ebselen, 4-hydroxy-2,2,6,6-tetramethylpiperidinyloxy (TEMPOL), superoxide dismutase, or combinations thereof. Various useful antioxidants include, but are not limited to, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, ebselen, and superoxide dismutase.

[0047] In one aspect of the first embodiment, chelating agents include, but are not limited to, disodium edetate, diethylene-triamine-pentaacetic acid (DTP A), iminodisuccinic acid, and ethylenediamine disuccinic acid.

[0048] In one aspect of the first embodiment, it relates to a stable powder composition is reconstituted with water to get solution or suspension, preferably at a concentration of about 200mg / ml.

[0049] In one aspect of the first embodiment, it relates to a unit-dose stable powder composition for an oral solution or suspension comprising: a) Trofinetide or salts; b) atleast one or more pharmaceutically acceptable excipients; wherein the composition is free of preservative, wherein the unit-dose powder composition is packed in unit dose packs like sachets or multi dose packs like HDPE or Glass or PET bottles.

[0050] In one aspect of the first embodiment, it relates to weight of Trofinetide in powder composition is selected from 2gm to 20gm. Preferably, the weight of Trofinetide in powder composition is 5gm, 6gm, 8gm, lOgm and 12gm. The unit-dose or multi-dose packs can be selected based on body weight of the patient.

[0051] In another aspect of the first embodiment, it relates to weight of Trofinetide in powder composition which is selected from 5gm, 6gm, 8gm. The unit-dose or multi -dose packs can be selected based on body weight of the patient.

[0052] In one aspect of the first embodiment, it relates to an oral Trofinetide powder composition comprising atleast one surfactant is selected from polysorbate, sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), poloxamer, span 80, sorbitan monostearate, certain Polyethylene Glycol (PEG) derivatives, and Tetrahydrofurfuryl alcohol polyethylene glycol ether (TPEG) or combinations thereof.

[0053] A second embodiment relates to a process for the preparation of a stable powder composition for oral solution or suspension comprising:

[0054] (a) mixing Trofinetide and one or more pharmaceutically acceptable excipients;

[0055] (b) fdling the Trofinetide powder composition into unit dose packs or multi dose packs. The unit dose packs can be sachets and multi dose packs can be HDPE or Glass or PET bottles.

[0056] A third embodiment relates to a stable powder composition for an oral solution or suspension which is useful in treating a variety of neurodegenerative disorders, autism spectrum disorders, and neurodevelopmental disorders.

[0057] In one aspect of the third embodiment, it relates to a stable powder composition for an oral solution or suspension which is useful for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older.

[0058] A fourth embodiment it relates to a stable ready-to-use oral solution comprising trofinetide and atleast one pharmaceutically acceptable excipients and process of making the same.

[0059] In one aspect of the fourth embodiment, it relates to a stable ready-to-use oral solution comprising trofinetide and atleast one pharmaceutically acceptable excipients, wherein the powder composition is devoid of antimicrobial preservatives, and process of making the same.

[0060] In present disclosure it provides a stable ready-to-use oral solution comprising trofinetide and atleast one or more pharmaceutically acceptable excipients which is useful in treating a variety of neurodegenerative disorders, autism spectrum disorders, and neurodevelopmental disorders.

[0061] In present disclosure it provides a stable ready-to-use oral solution useful for the treatment of Rett syndrome in adults and pediatric patients 2 years of age and older. The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

[0062] Table 01: Composition for Trofinetide Powder for solution 200mg / mL

[0063] Manufacturing procedure for PFOS:

[0064] 1. Trofinetide and other excipients like mannitol, sorbitol, xylitol, ascorbic acid, tartaric acid, disodium edetate, PEG 6000, maltitol, silicon dioxide, strawberry flavor, FD&C Red were accurately weighed and placed in a separate double-lined polybag.

[0065] 2. Slug the Trofinetide API with 13*00 mm round shape punches.

[0066] 3. (a). The slugged Trofinetide is passed through a mesh screen corresponding to ASTM #24 mesh and collected in a double-lined polybag;

[0067] (b). The excipients Maltitol, Sucralose, and Strawberry flavor were individually or collectively sifted through an ASTM #40 mesh and collected in a double-lined polybag;

[0068] (c). The materials obtained in steps 3(a) and 3(b) were co-sifted through an ASTM #24 mesh;

[0069] (d). FD&C Red No. 40 was separately sifted through an ASTM #60 mesh and collected in a double-lined polybag. 4. (a). The co-sifted blend obtained in step 3(c) was transferred into a 2-liter capacity octagonal blender and blended for a total of 150 revolutions, equivalent to approximately 10 minutes at 15 revolutions per minute (rpm);

[0070] (b). The sifted FD&C Red No. 40 obtained from step 3(d) is added to the previously blended mixture from step 4(a), and the resulting mixture was further blended for an additional 75 revolutions, corresponding to approximately 5 minutes at 15 rpm.

[0071] 5. The blended composition, hereafter transferred to suitable bottle for storage.

[0072] Table 02: Composition for Trofinetide ready-to-use oral solution 200mg / mL

[0073] Manufacturing procedure for ready-to-use oral solution 200mg / mL:

[0074] 1. Trofinetide and other excipients like mannitol, sorbitol, xylitol, ascorbic acid, tartaric acid, disodium edetate, PEG 6000, maltitol, silicon dioxide, strawberry flavor, Parabens and FD&C Red were accurately weighed and placed in a separate double-lined polybag. 2. Slug the Trofinetide API with 13*00 mm round shape punches.

[0075] 3. (a). The slugged Trofinetide was passed through a mesh screen corresponding to ASTM #24 and collected in a double-lined polybag; (b). The excipients Maltitol, Sucralose, and Strawberry flavor are individually or collectively sifted through an ASTM #40 mesh and collected in a double-lined polybag;

[0076] (c). The materials obtained in steps 3(a) and 3(b) are co-sifted through an ASTM #24 mesh;

[0077] (d). FD&C Red No. 40 is separately sifted through an ASTM #60 mesh and collected in a double-lined polybag.

[0078] 4. (a). The co-sifted blend obtained in step 3(c) is transferred into a 2-liter capacity octagonal blender and blended for a total of 150 revolutions, equivalent to approximately 10 minutes at 15 revolutions per minute (rpm);

[0079] (b). The sifted FD&C Red No. 40 obtained from step 3(d) is added to the previously blended mixture from step 4(a), and the resulting mixture is further blended for an additional 75 revolutions, corresponding to approximately 5 minutes at 15 rpm.

[0080] 5. The blended composition, hereafter referred to as PFOS, is introduced into purified water to yield a liquid formulation suitable for oral administration.

[0081] Table 03: Initial results of Trofinetide Powder for oral solution

[0082] BLQ- Below limit of quantification

[0083] ND- Not detected

[0084] Compositions of Ex 2 and Ex 4 were subjected stability at 25°C / 60%RH and 2-8 °C conditions and found that product was stable. Physical and chemical stability of Trofinetide powder for solution formulations were performed and results are given below. Table 04: Stability at 25°C / 60%RH and 2-8°C conditions of Trofinetide powder for solution formulations

[0085] BLQ- Below limit of quantification

[0086] ND- Not detected

[0087] Table 05: Initial results of Trofinetide ready-to-use oral solution

[0088] BLQ- Below limit of quantification

[0089] ND- Not detected

[0090] Compositions of Ex 2 and Ex 4 were subjected stability at 25°C / 60%RH and 2-8 °C conditions and found that product was stable. Physical and chemical stability of Trofinetide ready-to-use oral solutions were performed and results are given below.

[0091] Table 06: Stability at 25°C / 60%RH and 2-8°C conditions of Trofinetide oral solution

[0092] BLQ- Below limit of quantification

[0093] ND- Not detected

Claims

CLAIMS1. A stable powder for oral solution composition comprising of trofmetide and atleast one or more pharmaceutically acceptable excipients.

2. A stable powder for oral solution of claim 1 wherein the composition is devoid of preservatives.

3. A stable powder for oral solution of claim 1 comprising of crystalline or amorphous trofmetide.

4. A stable powder for oral solution of claim 1 comprising of one or more pharmaceutically acceptable excipients selected from one or more of diluents, sweeteners, flavors, dyes, antioxidants, glidants, chelating agents and combinations thereof.

5. A stable powder for oral solution of claim 1 is a unit or multi dose pack.

6. A stable powder for oral solution of claim 1 is a unit or multi dose pack comprising of weight of Trofmetide is selected from about 2gm to about 20gm.

7. A process of making a stable powder for oral solution composition of trofmetide and atleast one or more pharmaceutically acceptable excipients comprising of the steps: a) making slugs of trofmetide with one or more pharmaceutically acceptable excipients; b) passing slugs through screens; c) blending of step (b) powder with one or more pharmaceutically acceptable excipients; d) fdling of powder into a sachet or a bottle.

8. A stable ready-to-use oral solution composition comprising of trofmetide and atleast one or more pharmaceutically acceptable excipients wherein the composition is devoid of preservatives.

9. A stable ready-to-use oral solution composition of claim 8 comprising of trofmetide and one or more pharmaceutically acceptable excipients selected from one or more of diluents, sweeteners, flavors, dyes, antioxidants, glidants, chelating agents and combinations thereof.

10. A stable trofmetide composition of claims 1-9 are useful for treatment of Rett syndrome in adults and pediatric patients 2 years of age and older.

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