DESC:
FIELD OF INVENTION
The present invention relates to stable oral pharmaceutical composition comprising Pitolisant or its pharmaceutically acceptable salt. The invention further relates to a process for the preparation of the said pharmaceutical composition.

BACKGROUND
Narcolepsy is a disabling hypothalamic disorder that presents with a variety of sleep–wake and other symptoms. Excessive daytime sleepiness (EDS) is usually the most troublesome feature although significantly fragmented and disturbed nighttime sleep (DNS) is common with phenomena including sleep paralysis and hallucinatory experiences around sleep–wake transitions (hypnagogic and hypnopompic hallucinations). Whereas narcolepsy with typical cataplexy (type 1 narcolepsy, NT1) is considered a distinct entity, associated with hypocretin deficiency, narcolepsy without cataplexy (type 2 narcolepsy, NT2) is less clearly defined and when diagnosed following the current diagnostic criteria is a heterogeneous disorder. Although the precise aetiology of narcolepsy is unknown, most evidence suggests it is usually a sporadic acquired immune-mediated condition that develops in people who are genetically predisposed.

Worldwide prevalence estimates suggest that approximately 25–50 persons out of 100,000 are affected. Some recent studies indicate that narcolepsy may be less frequent. Narcolepsy potentially affects every aspect of daily life with considerable personal, social and economic consequences. As a result, quality of life measures of both patients and their families are significantly reduced. Narcolepsy is a rare chronic sleep disorder associated with debilitating excessive daytime sleepiness, cataplexy, sleep-related hallucinations and sleep paralysis. It affects approximately 0.02%-0.05% of various populations in European, USA and Asian countries. The onset of narcolepsy occurs most often between 10 to 25 years of age but can occur as early as 5 years or after 40 years of age. The observation of onset during late adulthood may be confounded by delays in diagnosis.

Pitolisant hydrochloride (Wakix®) is indicated for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy. It is a first-in-class agent to uniquely utilize the role of histamine in regulating wakefulness.

Pitolisant Hydrochloride

US patent No.7,169,928, discloses pitolisant or a pharmaceutically acceptably salts, hydrates, or hydrated salts, or their optical isomers, racemates, diastereoisomers or enantiomers.

US patent No. 8,207,197, discloses crystalline form of pitolisant hydrochloride salt and compositions thereof.

Although solid forms of pitolisant is known in the art, finding a better form having good physicochemical properties, desirable bioavailability, and advantageous pharmaceutical parameters remains a challenge.

There is a need for an improved method for loading a pitolisant or its pharmaceutical salts onto an inert substrate, which does not hinder the release of the pitolisant. The present invention provides such means.

There is also a need to provide an immediate release pharmaceutical composition comprising pitolisant or its pharmaceutically acceptable salt which is stable under storage conditions as per the recommendation of the ICH guidelines.

More recently, interest in the development of mesoporous inert substrates such as mesoporous silica materials as an oral drug delivery system are rapidly growing. Their large pore volume (up to 2.5 mL/g) in combination with a large specific surface area (up to 1,000 m2/g) results in a high drug-loading capacity. In addition, pore size and surface chemistry can be modified during synthesis to fit the needs of the user. The pore structure of mesoporous inert substrates such as mesoporous silica material is the key attribute to improving the dissolution rate of drugs. Because the pores are only a few times larger than drug molecules, the drug is confined and unable to crystallize. In this form, compounds exhibit higher dissolution rates when compared to their crystalline state.

The present invention is related to development of a simple, reproducible, and cost-effective process for preparing stable pharmaceutical compositions of pitolisant or its pharmaceutically acceptable salt. Further, pharmaceutical compositions prepared according to the manufacturing process of the present invention exhibit desired technical attributes such as dissolution and bioequivalence as comparable to commercially marketed pitolisant hydrochloride tablets (Wakix®).

The present invention provides a stable pharmaceutical amorphous composition comprising pitolisant or its pharmaceutical salts.

SUMMARY OF INVENTION
The present invention provides the following aspects, subject-matters, and preferred embodiments, which respectively taken alone or in combination, contribute to solving the object of the present invention:

We have surprisingly found a stable amorphous composition comprising pitolisant or its pharmaceutically acceptable salt.

In one embodiment, the present invention provides a composition comprising a mesoporous silica loaded with an active ingredient. The mesoporous silica may have a pore diameter of about 5 nm to about 30 nm.

In another embodiment, the present invention provides a composition comprising a mesoporous silica loaded with an active ingredient and a combination of a diluent and a disintegrant, and optional further excipients. The mesoporous silica may have a pore diameter of about 5 nm to about 30 nm.

In another embodiment, the present invention provides a composition comprising a mesoporous silica loaded with a pitolisant or its pharmaceutically acceptable salt and combination of microcrystalline cellulose (MCC) and crospovidone, and optionally further excipients. The mesoporous silica may have a pore diameter of about 5 nm to about 30 nm.

In another embodiment, examples of suitable pharmaceutical dosage forms are tablets, micro tablets, sachets, slugs, capsules, granulates or compressed granulates. Preferable dosage forms are tablets or capsules.

In another embodiment, the present invention provides composition comprising pitolisant or its pharmaceutically acceptable salt for an immediate release, wherein composition releases at least 50% drug within 5 minutes or at least about 85% drug within 15 minutes when measured in USP II (Paddle) apparatus having 1000 mL 0.1N HCl media with 75 rpm rotation at temperature 37 °C ± 0.5 °C.

The composition of the present invention is stable under ambient, long term, intermediate and accelerated stability conditions after at least about 6 months.

The present invention is directed to a process for adsorbing a pitolisant or its pharmaceutically acceptable salt onto a substrate, comprising the steps of (a) adding and mixing an inert adsorbent to a non-solid form of a crystalline pitolisant or its pharmaceutically acceptable salt, thereby forming a mixture and (b) drying the mixture to form a solid material.

The present invention is bioequivalent to commercial available pitolisant tablets Wakix® product.

DETAILED DESCRIPTION OF INVENTION
The invention will now be described in detail in connection with certain preferred and optional aspects, so that various aspects thereof may be more fully understood and appreciated.

The present invention provides a composition comprising pitolisant or its pharmaceutically acceptable salt.

The present invention also provides an amorphous composition comprising pitolisant or its pharmaceutical salts.

In one embodiment, the present invention provides composition comprising pitolisant or its pharmaceutically acceptable salt and an inert adsorbent.

In another embodiment, the present invention provides composition comprising pitolisant or its pharmaceutically acceptable salt absorbed on an inert adsorbent.

In another embodiment, the present invention provides composition comprising pitolisant or its pharmaceutically acceptable salt loaded on an inert adsorbent.

In one embodiment, the present invention provides a composition comprising a mesoporous silica loaded with an active ingredient. The mesoporous silica may have a pore diameter of about 5 nm to about 30 nm.

In another embodiment, the present invention provides a composition comprising a mesoporous silica loaded with an active ingredient and combination of a diluent and a disintegrant, and optional further excipients. The mesoporous silica may have a pore diameter of about 5 nm to about 30 nm.

In another embodiment, the present invention provides a composition comprising a mesoporous silica loaded with a pitolisant or its pharmaceutically acceptable salt and a combination of microcrystalline cellulose (MCC) and crospovidone, and optional further excipients. The mesoporous silica may have a pore diameter of about 5 nm to about 30 nm.

In another embodiment, the present invention provides a composition for an immediate release.

In one embodiment the present invention may be a coated or uncoated tablet, capsule, granule, powder.

In another embodiment, examples of suitable pharmaceutical dosage forms are tablets, micro tablets, sachets, slugs, capsules, granulates or compressed granulates. Preferable dosage forms are tablets or capsules.

In one embodiment, the dried solid crumbly or granular material of the present invention may be used in a core. The core may be compressed in the form of a tablet or as at least one layer of a multilayer tablet. In another embodiment the dried solid crumbly material may be deposited into a capsule form. In another embodiment, the dried solid crumbly or granular material may be used for direct administration from a sachet.

The core includes from about 5 to about 95 weight percent (wt.%) of the inert adsorbent.
In one embodiment, the core includes from about 5 to about 90 wt.% of the inert adsorbent. Preferably, the core includes from about 5 to about 75 wt.% of the inert adsorbent. Preferably, the core includes from about 5 to about 50 wt.% of the inert adsorbent.

In another embodiment, the composition comprises from about 5 to about 50 wt.% of the inert adsorbent.

In another embodiment, the composition comprises from 10 to 90%, or from 15 to 85%, or from 20 to 75%, or from 30 to 70%, or from 15 to 30%, or from 50 to 90%, or from 60 to 85%, of diluent.

In a further embodiment, the composition comprises from 3 to 20% of disintegrant, or from 5 to 20%, or from 5 to 15%, of disintegrant.

In further embodiment, the composition comprises from about 1% to about 15% pitolisant or its pharmaceutically acceptable salt.

In another embodiment, the present invention provides composition comprising pitolisant or its pharmaceutically acceptable salt for an immediate release, wherein composition releases at least 50% drug within 5 minutes or at least about 85% drug within 15 minutes when measured in USP II (Paddle) apparatus having 1000 mL 0.1N HCl media with 75 rpm rotation at temperature 37 °C ± 0.5°C.

In one of the embodiments, the immediate release composition releases at least about 70% of pitolisant within 30 minutes.

In another embodiment, the immediate release composition releases at least about 70% of pitolisant within 15 minutes.
In yet another embodiment, the immediate release composition releases at least about 80% of pitolisant within 30 minutes.

In yet another embodiment, the immediate release composition releases at least about 80% of pitolisant within 15 minutes.

In yet another embodiment, the immediate release composition releases at least about 85% of pitolisant within 30 minutes.
In yet another embodiment, the immediate release composition releases at least about 85% of pitolisant within 15 minutes.
In yet another embodiment, the immediate release composition releases at least about 90% of pitolisant within 30 minutes.

In yet another embodiment, the immediate release composition releases at least about 90% of pitolisant preferably within 15 minutes.
In yet another embodiment, the immediate release composition releases at least about 90% of pitolisant, preferably within 10 minutes.

In yet another embodiment, the immediate release composition releases at least about 90% of pitolisant most preferably within 5 minutes.
In certain embodiments, the degradation impurities in pharmaceutical composition of present invention are no greater than about 2% by weight, no greater than about 1.5% by weight, no greater than about 1% by weight, no greater than about 0.75% by weight, no greater than about 0.5% by weight, no greater than about 0.4% by weight, no greater than about 0.3% by weight, no greater than about 0.2% by weight, or no greater than about 0.1% by weight. In certain embodiments, the degradation impurity is detectable by HPLC (high performance liquid chromatography).

In certain embodiments, the degradation impurity includes, but is not limited to 1-(3-(3-(4-Chlorophenyl)propoxy)propyl)piperidine 1-oxide [hereinafter ‘N-Oxide Impurity’]; (3-(4-Chloro phenyl)-1-Propanol) [hereinafter ‘PTL 2(i) impurity’]; 1-Piperidinepropanol [hereinafter ‘PTL-1 impurity’]; 1-(3-( 4-Chlorophenyl)propyl)piperidine [hereinafter ‘PTL3-PRD impurity’]; 1-(3-(3-phenylpropoxy) propyl)piperidine [hereinafter ‘PTL-Deschloro impurity’].

In an another embodiment, the present invention provides stable pharmaceutical composition which is amorphous in nature comprising pitolisant or its pharmaceutically acceptable salt and mesoporous silica, since not limiting to any theory or hypothesis but the hygroscopic nature of drug and hydrophobic nature of mesoporous silica with enough pore diameter to accommodate the drug molecule without providing long range to drug molecule for crystallization leads to stabilization of the said composition.

In one aspect, pitolisant in the compositions of the present invention is not in the form of a solid dispersion.

In another aspect, pitolisant in the compositions of the present invention is not in the form of a co-crystals.

The pharmaceutical composition of the present invention is further characterized by X-ray powder diffraction technique. The powder X-ray powder diffraction pattern (Fig.1) shows product to be in amorphous form.

In another embodiment, the composition is generally presented as a unit-dose composition including from 1 to 200 mg of active pharmaceutical ingredient, more usually from 5 to 100 mg, for example 10 to 50 mg such as 10, 12.5, 15, 20, 25, 30 or 40 mg for a human patient. Most preferably unit doses include 20 or 40 mg of active pharmaceutical ingredient. Such a composition is normally taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active pharmaceutical ingredient administered is within the range of from 5 to 400 mg of active ingredient.

The composition of the present invention is stable under ambient, long term, intermediate and accelerated stability conditions after at least about 6 months.

In another embodiment, the present invention includes particle size of the pitolisant or its pharmaceutically acceptable salt, wherein D90 is less than about 100 µm, D50 is less than about 50 µm and D10 is less than 25 µm.

In one embodiment of the present invention relates to stable pharmaceutical composition comprising pitolisant or its pharmaceutically acceptable salts which is bioequivalent to the commercially available counterpart (Wakix®) after oral administration.

The present invention is directed to a process for adsorbing a pitolisant or its pharmaceutically acceptable salt onto a substrate, comprising the steps of (a) adding or mixing an inert adsorbent to a non-solid form of a crystalline pitolisant or its pharmaceutically acceptable salt, thereby forming a mixture; and (b) drying the mixture to form a solid material.

In another embodiment, the present invention is directed to a method of preparation of amorphous pitolisant or its pharmaceutically acceptable dosage form by adsorbing a pitolisant or its pharmaceutically acceptable salt onto a substrate, comprising the steps of (a) adding or mixing an inert adsorbent to a non-solid form of a pitolisant or its pharmaceutically acceptable salt, thereby forming a mixture; and (b) drying the mixture to form a solid material.

In another embodiment, the present invention also includes a method of taste masking a pitolisant or its pharmaceutically acceptable salt dosage form. The method comprising the steps of adsorbing pitolisant or its pharmaceutically acceptable salt onto a substrate, comprising the steps of (a) adding or mixing an inert adsorbent to a non-solid form comprising the pitolisant or its pharmaceutically acceptable salt, thereby forming a mixture; and (b) drying the mixture to form a solid brittle material.

In another embodiment, the present invention is directed to a method of preparation of amorphous pitolisant or its pharmaceutically acceptable dosage form by adsorbing a pitolisant or its pharmaceutically acceptable salt onto a mesoporous silica, comprising the steps of (a) adding or mixing an inert mesoporous silica to a non-solid form of a pitolisant or its pharmaceutically acceptable salt, thereby forming a mixture; and (b) drying the mixture to form a solid material.

In another embodiment, any suitable means for mixing may be used to mix the inert adsorbent to the non-solid form. For example, the inert adsorbent may be added to the non-solid dry form in a mixing kettle using an impeller mixer.

In another embodiment, the active ingredient such as pitolisant or its pharmaceutically acceptable salt is dissolved in an appropriate solvent to provide a solution which is then applied onto mesoporous material.

The non-solid form may be, for example, a solution, a suspension, an emulsion, a paste, or slurry. Additionally, the non-solid form may be aqueous based, solvent based, or lipid based.

In another embodiment, additionally, if so desired, the process may include the step of adding additional active pharmaceutical ingredient to the mixture prior to drying the mixture. This optional step would further add to the drug loading.

In another embodiment, drying of the mixture is performed using any suitable means. For example, the mixture may be air dried, oven dried, or fluid bed drying.

In another embodiment, in addition, the solid crumbly material may be further processed to reduce the particle size of the material. Any suitable process may be used to reduce the particle size.

The inert adsorbent is, for example but not limited to, laponite, bentonite, clays, magnesium aluminosilicate, magnesium aluminometasilicate, porous calcium silicate, and dicalcium phosphate and tricalcium phosphate, mesoporous silica, and mixtures thereof.

In one embodiment, the inert adsorbent is mesoporous silica, which has a higher bulk density and uniform particle size distribution as compared to fumed silica with a unique morphology. Mesoporous silica may be sourced from but not limited to W.R. Grace and Company of Maryland, which markets its product under the tradename SYLOID®.

In one embodiment, the composition contains pitolisant or its pharmaceutically acceptable salt absorbed onto an inert adsorbent. The inert adsorbent may be but not limited to, for example, silicon dioxide (Syloid® 63FP, Syloid® XDP 3050, Syloid® XDP 3150, Parteck® SLC, Parteck® SLC 500 etc.) In some embodiment, the Colloidal silicon dioxide may also be blended with the active and inert adsorbent.

In another embodiment, the inert adsorbent is mesoporous silica, which has a drug loading capacity of about 1% to about 50%, more preferentially up to about 30%.

In another embodiment, the present invention includes particle size of the said mesoporous silica, wherein the average particle size is less than 200 µm.

The terms “drug” or “active pharmaceutical ingredient” refers to pitolisant or its pharmaceutically acceptable salt and are equivalent terms. Pitolisant HCl that may be used as the input of this invention may be obtained by any process including the process described in the art. The input material is either crystalline or amorphous.

The terms "drug-loaded" and "loaded", when used in relation to a mesoporous silica are meant to be equivalent terms.

The term "pharmaceutically acceptable salt" includes suitable salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Examples of such salts that can be suitable in contexts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Examples of salts derived from inorganic bases include, but are not limited to, aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, and zinc.

The terms "mesopore" or "mesoporous" and the like refer to porous structures having pore sizes in the range of 2 nm to 50 nm. No spatial organization or method of manufacture is implied by these terms. Mesoporous silicas have pore sizes in the range of 2 nm to 30 nm, or in the range of 2 nm to 20 nm, or in the range of 4 nm to 16 nm, or in the range of 6 nm to 14 nm.

The term "about" when used in relation to a numerical value has the meaning generally known in the relevant art. In certain embodiments the term "about" may be left out or it may be interpreted to mean the numerical value±10%; or ±5%; or ±2%; or ±1%.

The term "immediate release" (IR) meaning, for example, a release of at least 60% of the drug under physiological conditions (pH, temperature), such as within 60 minutes or less, such as within 30 or less, or within 20 minutes or less, or within 15 minutes or less. An immediate release drug product is considered rapidly dissolving when no less than 85% of the drug substance dissolves within 30 minutes in a volume of 900 ml or less in media of varying pH.

The term, "disintegrant" is an excipient that hydrates a pharmaceutical composition and aids in tablet dispersion. Examples of disintegrants include but not limited to crospovidone, sodium croscarmellose and/or sodium starch glycolate, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC), sodium carbonate, modified starch, starch 1500 and sodium hydrogen carbonate.

The term, "diluent" or "filler" is an excipient that adds bulkiness to a pharmaceutical composition. Examples of diluent or filler include but not limited to calcium phosphate, dicalcium phosphate, tricalcium phosphate, calcium sulfate, anhydrous lactose, spray dried lactose, hydrated lactose, cellulose, spray dried microcrystalline cellulose, spray dried combinations comprising microcrystalline cellulose and lactose, silicified microcrystalline cellulose, kaolin, bentonite, mannitol, starch, magnesium carbonate, sorbitol, sucrose, inositol, compressible sugar, trehalose and xylitol, and mixtures thereof.

The term, “coat” or “coating” or “coated” are equivalent terms and refers to film coating on to uncoated tablets or granules or powder. The example of coating excipients includes but not limited to those known in the art, such as cellulose derivatives (hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose and their derivatives), acrylic and methacrylic copolymers of different molecular weights, and mixtures thereof, water-soluble polymers for instance, aminoalkyl methacrylate copolymer E, hypromellose, methyl cellulose, methyl-hydroxyethyl cellulose, Opadry, calcium carmellose, sodium carmellose, polyvinyl pyrrolidone, polyvinyl alcohol, dextrin, pullulan, gelatin, agar and gum Arabic, among others. The coating layers over the tablet may be applied as solution/dispersion of coating ingredients using conventional techniques known in the art selected from spray coating in a conventional coating pan or fluidized bed processor, dip coating, and the like.

The lubricant of the present invention is known or determinable by those skilled in the art and includes, but is not limited to, at least one of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax and sodium stearyl fumarate. Preferably, the lubricant of the present invention is present in an amount of 0.1 to 5% by weight, relative to the weight of the solid formulation.

The term, “core” refers to the dried solid crumbly or granular material having drug loaded mesoporous silica.

The term "bioequivalent" means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. In practice, two products are considered bioequivalent if the 90% confidence interval of the Cmax, AUC, or, optionally, Tmax is within the range of 80.00% to 125.00%.

The pharmaceutical composition of the present invention may be prepared by various methods such as wet granulation, dry granulation, or direct compression.
In another embodiment of the invention, the process for preparing the said compositions comprise steps of:
Step 1. Dissolve pitolisant HCl in acetone or dichloromethane or ethanol (suitable solvent) under stirring to form a clear solution.
Step 2. Load Step 1 solution on mesoporous silica under stirring at product temperature 40°C.
Step 3. Dry the step 2 material at 40°C under constant stirring till getting the desired LOD.
Step 4. Sift the dried granules of step-3 using mesh ASTM #30.
Step 5. Extra granular material MCC, and crospovidone using suitable mesh and blend along with step 4 milled granules in a suitable blender.
Step 6. Sift lubricant magnesium stearate using suitable mesh and lubricate the step- 5 blended material in a suitable blender.
Step 7. Compress the tablets using blend of step-6 using suitable punches.
Step 8. Prepare opadry coating dispersion using purified water and coat the step-7 tablets in a suitable perforate coating pan. Dry the coated tablets.

The following examples are meant to illustrate the present invention and should not be construed as limiting its scope.

EXAMPLES
Immediate release tablet composition
Example 1: Immediate release 20 mg pitolisant hydrochloride (equivalent to 17.8 mg pitolisant) tablet composition

Table 1: Immediate release 20 mg pitolisant hydrochloride (equivalent to 17.8 mg pitolisant) tablet composition
Sr. No. Strategy I II
Ingredients mg/tablet % w/w mg/tablet % w/w
Intragranular part:
1 Silicon Dioxide (Syloid XDP) - - 46.600 25.26
2 Silicon Dioxide (Parteck SLC) 46.600 25.26 - -
Binder solution:
5 Pitolisant Hydrochloride 20.000 10.84 20.000 10.84
6 Acetone or Methylene chloride or Ethanol
Q. S. - Q. S. -
Extragranular material
9 Microcrystalline Cellulose Avicel 200LM 102.600 55.61 - -
Avicel 200 - - 109.800 59.51
10 Crospovidone, 9.000 4.88 1.800 0.98
11 Magnesium stearate 1.800 0.98 1.800 0.98
Total weight 180.000 180.000 -
Coating
12 Opadry White (85F18422) 4.500 2.44 4.500 2.44
13 Purified water Q. S. - Q. S. -
Total weight 184.500 - 184.500 -

Example 2: Immediate release 5 mg pitolisant hydrochloride (equivalent to 4.45 mg pitolisant) tablet composition

Table 2: Immediate release 5 mg pitolisant hydrochloride (equivalent to 4.45 mg pitolisant) tablet composition
Sr. No. Strategy I II
Name of the Ingredients mg/tablet % w/w mg/tablet % w/w
Intragranular part:
1 Silicon Dioxide (Syloid XDP) - - 11.650 25.26
2 Silicon Dioxide (Parteck SLC) 11.650 25.26 - -
Binder solution:
5 Pitolisant Hydrochloride 5.000 10.84 5.000 10.84
6 Acetone or Methylene chloride or Ethanol Q. S. - Q. S. -
Extragranular material
9 Microcrystalline Cellulose Avicel 200LM 25.650 55.61 - -
Avicel 200 - - 27.450 59.51
10 Crospovidone, 2.250 4.88 0.450 0.98
11 Magnesium stearate 0.450 0.98 0.450 0.98
Total weight 180.000 180.000 -
Coating
12 Opadry White (85F18422) 1.125 2.44 1.125 2.44
13 Purified water Q. S. - Q. S. -
Total weight 46.125 - 46.125 -

Example 3: Manufacturing process for pitolisant tablet composition of example 1 and 2.
Step 1: Dissolve Pitolisant HCl in Acetone or Methylene chloride or Ethanol (Suitable Solvent) under stirring to form a clear solution.
Step 2: Load Step 1 solution on Silicon Dioxide i.e. Syloid XDP 3150 or Parteck SLC.
Step 3: Dry the step 2 material at 40°C under constant stirring tilll getting the desired LOD.
Step 4: Sift the dried granules of step-3 using mesh ASTM #30.
Step 5: Extra granular material MCC, and Crospovidone using suitable mesh and blend along with step 4 milled granules in a suitable blender
Step 6: Sift lubricant Magnesium stereate using suitable mesh and lubricate the step- 5 blended material in a suitable blender.
Step 7: Compress the tablets using blend of step-6 using suitable punches.
Step 8: Prepare opadry coating dispersion using purified water and coat the step-7 tablets in a suitable perforate coating pan. Dry the coated tablets.

Dissolution Profile:
The tablets were prepared as per examples 4 to 6 and in-vitro dissolution analyzed using USP type II paddle apparatus, at 75 rpm, using 1000 mL, 0.1N HCL media at temp. 37°C ± 0.5°C

Table 3: Dissolution profile of pitolisant tablets of examples 1 and 2
Time
(Min.) % Cumulative Dissolution Profile
Example 1 Example 2
5 91 70
10 102 89
15 104 95
20 104 95
30 104 98
45 104 98
60 104 98

It is evident from table 3 that the pitolisant compositions of the present invention provided the desired immediate release dissolution in 5 minutes to 30 minutes.

Stability Studies:
Tablet composition in accordance with example 4 and 5, containing 17.8 mg and 4.45 mg of pitolisant respectively, were packed in HDPE bottle with desiccant. These packs were subjected to accelerated storage conditions of 40°C/75%RH for a period of six months. The tablets were analyzed for water content, in-vitro dissolution, related substances or degradation products and assay.

Table 4: In vitro release, % assay, water content and degradation impurity of 17.8 mg pitolisant tablets of example 1 packaged in HDPE bottle with desiccant after 1, 3 and 6-month stability at 40°C/75% RH.
Tests Initial 1M 3M 6M Limit
Water Content 4.02 2.63 2.53 2.84 NMT 8.0
Dissolution: % In vitro release in 1000ml, 0.1N HCl, USP Type II (Paddle), 75RPM at temp. 37°C ± 0.5°C
Time (min) Initial 1M 3M 6M Limit
5 91 92 95 86 -
10 102 100 101 97 -
15 104 101 102 99 NLT 80%
20 104 101 103 99 -
30 104 101 103 99 NLT 80%
45 104 101 102 99 -
60 104 102 102 99 -
Assay (%)
Each Tablet Contains Initial 1M 3M 6M Limit
Pitolisant 17.95 18.23 18.05 18.18 Between 16.02 mg to 19.58 mg
% Label Claim 100.8 102.4 101.4 102.1 90.0 to 110.0% of Lable Claim
Degradation Products
Degradation Products by HPLC (%) Initial 1M 3M 6M Limit
N Oxide ND 0.002 0.016 0.022 NMT 0.5
PTL2(i) 0.006 0.023 0.020 0.025 NMT 0.5
Highest Unspecified degradation products 0.062(1.24) 0.064(1.30) 0.068(1.26) 0.066(1.27) NMT 0.2
Total Impurity 0.156 0.175 0.186 0.181 NMT 2.0
BQL: Below quantification limit
NMT: Not more than
NLT: Not less than
ND: Not Detected

Table 5: In vitro release, % assay, water content and degradation impurity of 4.45 mg pitolisant tablets of example 2 packaged in HDPE bottle with desiccant after 1, 3 and 6-month stability at 40°C/75% RH.
Tests Initial 1M 3M 6M Limit
Water Content 5.51 2.40 1.98 3.06 NMT 8.0
Dissolution: % In vitro release in 1000ml, 0.1N HCl, USP Type II (Paddle), 75RPM at temp. 37°C ± 0.5°C
Time (min) Initial 1M 3M 6M Limit
5 70 72 59 54 -
10 89 88 83 77 -
15 95 93 90 87 NLT 80%
20 95 95 93 92 -
30 98 97 95 98 NLT 80%
45 98 98 97 99 -
60 98 96 97 100 -
Assay(%)
Each Tablet Contains Initial 1M 3M 6M Limit
Pitolisant 4.43 4.42 4.42 4.39 Between 16.02 mg to 19.58 mg
% Label Claim 99.6 99.3 99.2 98.7 90.0 to 110.0% of Lable Claim
Degradation Products
Degradation Products by HPLC(%) Initial 1M 3M 6M Limit
N Oxide 0.043 0.002 0.018 0.030 NMT 0.5
PTL2(i) 0.018 0.023 0.022 0.032 NMT 0.5
Highest Unspecified degradation products 0.064(1.26) 0.061(1.29) 0.065(1.26) 0.064(1.27) NMT 2.0
Total Impurity 0.194 0.163 0.185 0.195 NMT 2.0
BQL: Below quantification limit
NMT: Not more than
NLT: Not less than
ND: Not Detected

The stability data in table 4 and 5 reveals that there is no significant change in the in-vitro dissolution, related substances / degradation products and assay value, of the pitolisant tablets, in HDPE with desiccant pack on storage. The said tablets were found to be stable for a period of at least 6 months at accelerated storage conditions (40°C/75%RH) as per the recommendation of the ICH guidelines.
Bioequivalence study:
An Open label, balanced, randomized, Single-Dose, Two-Treatment, Two-Sequence, Two-Period Crossover bioequivalence study of pitolisant tablets 17.8 mg of example 4 (Test) was carried out in normal healthy human subjects using Wakix® (Pitolisant) tablets 17.8 mg of Harmony Biosciences LLC as the reference product (Reference).

Statistical analyses will be done using SAS® software Version 9.4 or higher version of SAS Institute Inc., USA. The log-transformed pharmacokinetic parameters Cmax, AUC0-t or AUClast and AUC0-8 for Pitolisant will be analysed using ANOVA. The Intra subject CV, Power, Ratio analysis, and its 90% CI will be computed for log transformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-8 for Pitolisant. The bioequivalence studies were carried out under fasting (n=16) and fed conditions (n=16).

Table 6: Bioequivalence study data
Parameters Fasting Condition Fed Condition
% Ratio 90 % CI for log
transformed data % Ratio 90 % CI for log
transformed data
Test/Reference Lower Upper Test/Reference Lower Upper
Cmax 105.31 96.26 115.21 93.63 82.62 106.10
AUClast 99.69 90.21 110.16 100.82 90.82 111.91
AUC0-8 99.61 89.37 111.03 101.16 90.29 113.34

Based on the results of the bioequivalence studies, the pitolisant tablets were found to be bioequivalent to commercially available Wakix® tablets.

Thus, the compositions of the present invention provide the desired immediate release of pitolisant and was found to be bioequivalent to Wakix® tablets. The composition was found to be stable under accelerated conditions (40°C/75%RH) for a period of at least 6 months.
,CLAIMS:1. A pharmaceutical composition comprising
a) pitolisant or its pharmaceutically acceptable salt; and
b) Mesoporous silica.

2. The composition as claimed in claim 1, wherein mesoporous silica is present in an amount from about 5% to about 95%.

3. The composition as claimed in claim 1, wherein pitolisant or its pharmaceutically acceptable salt present in an amount about 1% to about 15%.

4. The composition as claim 1, wherein composition further comprises at least one excipient selected from the group consisting of diluent, binder, disintegrating agent, lubricant and glidant.

5. The composition as claimed in claim 4, wherein disintegrating agent is selected from crospovidone, sodium croscarmellose and/or sodium starch glycolate, pregelatinized starch, low-substituted hydroxypropyl cellulose (L-HPC), sodium carbonate, modified starch, starch 1500, sodium hydrogen carbonate or mixtures thereof.

6. The composition as claimed in claim 4, wherein diluent or filler is selected from calcium phosphate, dicalcium phosphate, tricalcium phosphate, calcium sulfate, anhydrous lactose, spray dried lactose, hydrated lactose, cellulose, spray dried microcrystalline cellulose, spray dried combinations comprising microcrystalline cellulose and lactose, silicified microcrystalline cellulose, kaolin, bentonite, mannitol, starch, magnesium carbonate, sorbitol, sucrose, inositol, compressible sugar, trehalose and xylitol, or mixtures thereof.

7. The composition as claimed in claim 1, wherein the composition is in form of powder, granules, pellets, mini-tablets, tablets, or capsules.

8. The composition as claimed in claim 7, wherein the tablet is in form of immediate release tablet.

9. The composition as claimed in claim 1, wherein the composition releases at least 70% of pitolisant within 30 minutes.

10. A method of preparation of amorphous pitolisant comprises: adsorbing a pitolisant or its pharmaceutically acceptable salt onto a mesoporous silica,
wherein the absorbing comprises the steps of:
(a) adding or mixing an inert adsorbent to a non-solid form of a crystalline pitolisant or its pharmaceutically acceptable salt, thereby forming a mixture; and
(b) drying the mixture to form a solid material.

11. The composition as claimed in claim 7, wherein the composition is bioequivalent to commercially available Wakix® product.

12. The composition as claimed in claim 1, wherein degradation impurities no greater than about 2% by weight, no greater than about 1.5% by weight, no greater than about 1% by weight, no greater than about 0.75% by weight, no greater than about 0.5% by weight, no greater than about 0.4% by weight, no greater than about 0.3% by weight, no greater than about 0.2% by weight, or no greater than about 0.1% by weight.

13. The composition as claimed in claim 12, wherein the degradation impurity comprises one or more impurities selected from 1-(3-(3-(4-Chlorophenyl)propoxy)propyl)piperidine 1-oxide; (3-(4-Chloro phenyl)-1-Propanol); 1-Piperidinepropanol; 1-(3-( 4-Chlorophenyl)propyl)piperidine; 1-(3-(3-phenylpropoxy) propyl)piperidine.