DESC:SUSTAINED RELEASE COMPOSITION OF HYDROXYZINE AND IT’S PROCESS

TECHNICAL FIELD OF THE INVENTION
The present invention relates to sustained release compositions of Hydroxyzine or a pharmaceutically acceptable salt or a solvate thereof. The present invention also relates to sustained release compositions of Hydroxyzine hydrochloride comprising core matrix, barrier coating and film coating with less sedation. The invention also relates to a method of preparation of such compositions of Hydroxyzine or pharmaceutically acceptable salts or solvate thereof.
BACKGROUND OF THE INVENTION
Hydroxyzine (hye drox' i zeen) is a first generation antihistamine that is used mostly to treat itching and nausea. Because of its sedating effects, hydroxyzine is also used for anxiety, tension and as a mild sleeping aid. Hydroxyzine belongs to the piperazine class of antihistamines (with cyclizine and meclizine) which are more commonly used for itching, nausea and anxiety than for their effects on symptoms of allergic rhinitis or coryza. Hydroxyzine was approved for use in the United States in 1956 and continues to be widely used. It is available as tablet and capsule dosage forms of 10, 25, 50 and 100 mg under the trade names Atarax and Vistaril. Hydroxyzine hydrochloride is chemically known as 1-(p-chlorobenzhydryl) 4-[2-(2-hydroxyethoxy)-ethyl] piperazine dihydrochloride with the chemical formula C21H27ClN2O2 • 2HCl, molecular weight of 447.83 g/mol and has the following chemical structure:

U.S. Patent No. 2,899,436 A discloses Hydroxyzine product generically.
U.S. Patent No. 3,577,514A discloses sustained release pharmaceutical tablet composition of Hydroxyzine characterized by a substantially constant rate of drug release comprising; (a) medicament; (b) a hydrophobic dissolution retardant; (c) an acid-insoluble release agent; and (d) a water-soluble or dispersible binder.
WO 2001/051033 A1 discloses solid pharmaceutical composition for oral administration, allowing controlled release by at least one active substance, consisting of a homogeneous mixture including: a) said at least one substance; b) between 5 and 95% by weight, relative to the total weight of the composition, of at least one matrix excipient; c) between 2 and 50% by weight, relative to the total weight of the composition, of at least one enteric-soluble polymer; and d) between 0.5 and 50% by weight, relative to the total weight of the composition, of at least an alkalizing agent soluble in an aqueous phase under pH conditions physiological. This publication discloses Hydroxyzine as a substance in a laundry list.
U.S. Publication No. 2021/0228488 A1 discloses an extended release pharmaceutical composition comprising plurality of modified release units wherein each unit comprises of an active agent core comprising at least one pharmaceutically active agent and at least one pharmaceutically acceptable excipient, substantially coated with at least one release-controlling agent. Hydroxyzine is disclosed as active agent.
Ghosh et al., Asian Journal of Pharmaceutics, 2014, 230-236 discloses hydroxyzine hydrochloride sustained release microspheres by ionotropic gelation technique using Carbopol 934P.
The prior arts described above discloses sustained release pharmaceutical compositions comprising medicament (Hydroxyzine), hydrophobic dissolution retardant, an acid-insoluble release agent, a water-soluble or dispersible binder, controller release formulation comprising substance, matrix excipient, enteric-soluble polymer, alkalizing agent, extended release pharmaceutical composition comprising plurality of modified release units, hydroxyzine hydrochloride sustained release microspheres. But none of the prior arts are feasible at higher manufacturing capacities. Further, sedation and drowsiness are the major side effects observed with available immediate release formulations of Hydroxyzine Hydrochloride available in market.
To overcome these side effects and manufacturing problems, inventors of the present invention have developed sustained release oral composition of Hydroxyzine or its pharmaceutically acceptable salt. Further, the inventors of the present invention provide sustained release tablet composition of Hydroxyzine hydrochloride which is targeted to release the drug with blunted Cmax with plasma concentration values ranging between 40±12 ng/mL, thus the formulation of the present invention has a potential to reduce the exposure to high levels of the drug, while maintaining the efficacy. The inventors of the present invention also provide method of preparation of sustained release tablet composition of Hydroxyzine or its pharmaceutically acceptable salts using wet granulation and direct compression.
OBJECT OF THE INVENTION
The main aspect of the present invention is to provide sustained release oral pharmaceutical compositions of Hydroxyzine or its pharmaceutically acceptable salt or a solvate thereof with less sedative effect.
In another aspect, the present invention relates to sustained release oral pharmaceutical compositions comprising Hydroxyzine or its pharmaceutically acceptable salts as active ingredient along with other pharmaceutically acceptable excipients.
In yet another aspect, the present invention relates to the oral pharmaceutical compositions of the present invention include tablets, capsules, mini-tablets, granules.
In another aspect, the present invention relates to sustained release tablet composition of Hydroxyzine or its pharmaceutically acceptable salt comprising a) core matrix, b) barrier coating and c) film coating.
In yet another aspect, the present invention relates to sustained release tablet composition comprising Hydroxyzine or its pharmaceutically acceptable salt, high viscosity polymers, diluents, binder, filler, glidant, water-insoluble release modifier, pore forming agent, lubricant, solvents as pharmaceutically acceptable excipients.
In still another aspect, the present invention relates to sustained release tablet composition of Hydroxyzine or its pharmaceutically acceptable salt comprising a) core matrix containing active ingredient, high viscosity polymers, diluent, binder, glidant, lubricant, solvents, b) barrier coating containing water-insoluble release modifier, pore forming agent, solvents and c) film coating containing opadry film coating and solvent.
In yet another aspect of the present invention relates to process for the preparation of sustained release tablet composition of Hydroxyzine or its pharmaceutically acceptable salt comprising the steps of sifting, wet granulation, drying, milling, blending, lubrication, direct compression, barrier coating, film coating and packing.
In yet another aspect of the present invention provides a sustained release composition of Hydroxyzine or its pharmaceutically acceptable salt which is targeted to release the drug with blunted Cmax with plasma concentration values ranging between 40±12 ng/mL, thus has a potential to reduce the exposure to high levels of the molecule, while still maintaining efficacy.
In yet another aspect, the compositions of the present invention when subjected to in vitro changeover dissolution study exhibits following release profile:
i) releases not more than 35% in 1 hour, in 900 ml of 0.01N HCl medium at 50 rpm and 37°C using USP type II apparatus, and
ii) releases at least about 40% - 85% in 4 hours and not less than 85% in 10 hours, in 900 ml of pH 6.8 phosphate buffer medium at 50 rpm and 37°C using USP type II apparatus.

SUMMARY OF THE INVENTION
Accordingly, the present invention relates to sustained release tablet of Hydroxyzine or a pharmaceutically acceptable salt or a solvate thereof to overcome the side effects associated with Hydroxyzine Hydrochloride immediate release tablet.
In another aspect, the present invention relates to sustained release oral pharmaceutical compositions comprising Hydroxyzine or its pharmaceutically acceptable salts as active ingredient along with other pharmaceutically acceptable excipients.
In yet another aspect, the present invention relates to the oral pharmaceutical compositions of the present invention include tablets, capsules, mini-tablets, granules.
In another aspect, the present invention relates to sustained release tablet composition comprising Hydroxyzine or a pharmaceutically acceptable salt as active ingredient and pharmaceutically acceptable excipients.
In yet another aspect, the present invention relates to sustained release tablet composition comprising Hydroxyzine or a pharmaceutically acceptable salt as active ingredient, high viscosity polymers, diluents, binder, filler, glidant, water-insoluble release modifier, pore forming agent, lubricant, solvents as pharmaceutically acceptable excipients.
In still another aspect, the present invention relates to sustained release tablet composition comprising a) core matrix, b) barrier coating and c) film coating.
In another aspect, the present invention relates to sustained release tablet composition of Hydroxyzine or a pharmaceutically acceptable salt comprising a) core matrix comprising active ingredient, high viscosity polymers, diluent, binder, glidant, lubricant, solvents, b) barrier coating comprising water-insoluble release modifier, pore forming agent, solvents and c) film coating comprising opadry film coating and solvent.
In yet another aspect, the present invention relates to sustained release tablet composition of Hydroxyzine or a pharmaceutically acceptable salt comprising a) core matrix comprising Hydroxyzine or a pharmaceutically acceptable salt as active ingredient, Hypromellose K15MCR, Hypromellose K4MCR, Hypromellose E4M, Hypromellose E10M as high viscosity polymers, Lactose monohydrate, mannitol, dibasic calcium phosphate as diluent, Hydroxypropyl cellulose (Kluel EXF), polyvinylpyrrolidone (PVP), copovidone as binder, porous silica (Syloid® 244 FP silica), colloidal silicon dioxide, cellulose as glidant, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulfate as lubricant, isopropyl alcohol, purified water as solvents, b) barrier coating containing ethyl cellulose, polyvinyl acetate, polyvinyl chloride as water-insoluble release modifier, Hydroxypropyl cellulose (Kluel EF), glycerol, propylene glycol as pore forming agent, isopropyl alcohol, acetone as solvents and c) film coating containing Opadry AMB white as opadry film coating which comprises polyvinyl alcohol-part hydrolyzed, titanium dioxide, talc, lecithin and polyvinyl alcohol-part hydrolyzed, purified water as solvent or Opadry AMB II which comprises Polyvinyl alcohol, Talc, Titanium dioxide, GMCC Type-1 and sodium lauryl sulfate.
Another aspect of the present invention relates to provide process for the preparation of oral sustained release pharmaceutical compositions of Hydroxyzine or its pharmaceutically acceptable salts.
Another aspect of the present invention relates to provide process for the preparation of sustained release tablet composition of Hydroxyzine hydrochloride comprising the steps of dispensing, sifting, wet granulation, drying, milling, blending, lubrication, direct compression, barrier coating, film coating and packing.
In another aspect, the present invention relates to sustained release tablet composition comprising:
a) core matrix:
20% to 60% (w/w) of active ingredient,
1% to 40% (w/w) of high viscosity polymers,
20% to 70% (w/w) of diluent,
0.05% to 10% (w/w) of binder,
0.05% to 5% (w/w) of glidant,
0.01% to 5% (w/w) of lubricant, and
QS of solvents.
b) barrier coating:
0.05% to 10% (w/w) of water-insoluble release modifier,
0.05% to 10% (w/w) of pore forming agent, and
QS of solvents, and/or
c) film coating:
0.1% to 5% (w/w) of opadry film coating, and
QS of solvent.

In yet another aspect, the present invention relates to sustained release tablet composition Hydroxyzine hydrochloride comprising:
a) core matrix:
20% to 60% (w/w) of Hydroxyzine hydrochloride,
1% to 40% (w/w) of Hypromellose,
20% to 70% (w/w) of lactose monohydrate,
0.1% to 10% (w/w) of Hydroxypropyl cellulose,
0.05% to 5% (w/w) of porous silica,
0.01% to 5% (w/w) of magnesium stearate, and
QS of isopropyl alcohol and purified water.
b) barrier coating:
0.05% to 10% (w/w) of ethyl cellulose,
0.05% to 10% (w/w) of hydroxypropyl cellulose,
QS of isopropyl alcohol and acetone, and/or
c) film coating:
0.1% to 5% (w/w) of Opadry, and
QS of purified water.

In yet another aspect, the present invention relates to process for the preparation of sustained release tablets, wherein the process comprising steps of:
(a) sifting and mixing active ingredient, high viscosity polymers, binder and diluent,
(b) transferring co-sifted material into rapid mixer granulator (RMG), dry mixing and adding the mixture of solvents ,
(c) drying the wet granules in Fluid bed processor, milling the dried granules
(d) sifting the glidant using suitable screen and mixing with obtained dried milled granules of step (d) followed by blending and lubricating
(e) compressing the lubricated blend using suitable punch toolings in compression machine,
(f) barrier coating is applied over the blend of step (e) followed by film coating and packaging

In yet another aspect, the present invention relates to process for preparing sustained release tablet composition Hydroxyzine hydrochloride, wherein the process comprising the steps of:
(a) sifting and mixing Hydroxyzine hydrochloride, Hypromellose, Hydroxypropyl cellulose and lactose monohydrate,
(b) transferring co-sifted material into rapid mixer granulator (RMG), dry mixing
(c) drying the wet granules and milling the dried granules followed by sifting the porous silica using suitable screen and mixing with obtained dried milled granules of step (d) followed by blending and lubricating
(d) compressing the lubricated blend using suitable punch toolings in compression machine,
(e) barrier coating is applied over the blend of step (e) over uncoated tablets, followed by film coating and packaging

In yet another aspect, the present invention relates to process for the preparation of sustained release tablets, wherein the process comprising steps of:
(a) sifting and mixing active ingredient, high viscosity polymers, binder and diluent,
(b) transferring co-sifted material into rapid mixer granulator (RMG), followed by dry mixing and milling
(c) sifting the glidant using suitable screen and mixing with obtained dried milled granules of step (d) followed by blending and lubricating
(d) barrier coating is applied over the blend of step (c) followed by film coating and filling the granules of step into capsules or sachets or compressing into minitablets.

In yet another aspect, the compositions of the present invention when subjected to in vitro changeover dissolution study exhibits following release profile:
i) releases not more than 35% in 1 hour, in 900 ml of 0.01N HCl medium at 50 rpm and 37°C using USP type II apparatus, and
ii) releases at least about 40% - 85% in 4 hours and not less than 85% in 10 hours, in 900 ml of pH 6.8 phosphate buffer medium at 50 rpm and 37°C using USP type II apparatus.

DESCRIPTION OF INVENTION
The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

The term “Hydroxyzine” as used in the context of the present specification is an active ingredient and relates to the free base form, acid form, salt form, polymorphic crystalline or amorphous form, solvates, ethers, esters, etc. Hydroxyzine is an antihistaminic drug and used for treating allergic skin reactions. It is also used as sedative to treat anxiety and tension.
"Salts" include derivatives of an active agent, wherein the active agent is modified by making acid or base addition salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid addition salts of basic residues such as amines; alkali or organic addition salts of acidic residues; and the like, or a combination comprising one or more of the foregoing salts. The pharmaceutically acceptable salts include salts and the quaternary ammonium salts of the active agent. For example, acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; other acceptable inorganic salts include metal salts such as sodium salt, potassium salt, cesium salt, and the like; and alkaline earth metal salts, such as calcium salt, magnesium salt, and the like, or a combination comprising one or more of the foregoing salts.
In still another aspect, the present invention relates to sustained release tablet of Hydroxyzine or a pharmaceutically acceptable salt or a solvate thereof to overcome the side effects associated with Hydroxyzine Hydrochloride immediate release tablet.
The concentration of active ingredient used in the present invention ranges from 20% to 60% (w/w) to the total concentration, most preferably ¬¬¬¬¬20 to 28% (w/w).
The term “pharmaceutically acceptable excipients” include, but not limited to, one or more of high viscosity polymers, diluent, glidant, lubricant, water-insoluble release modifier, binder, solvent and the like.
The term “oral pharmaceutical compositions” as used herein includes but not limited to all forms of orally administered dosage forms, e.g. a monolithic one, e.g. a tablet or a capsule, or a multiparticulate one, e.g. granules, pellets or microspheres. Multiparticulate compositions may be further processed to form a monolithic dosage form. Preferably, said pharmaceutical composition is in the form of a tablet.
Suitable “high viscosity polymers” may be selected from polymers having molecular weight of greater than 50,000 daltons. High viscosity HPMC polymers include E4M, E10M, K4MCR, K15MCR and K100M. Other polymers include copovidone, hypromellose phthalate (hydroxypropylmethylcellulose phthalate, HPMCP), hypromellose acetate succinate (hydroxypropylmethylcellulose acetate succinate, HPMCAS), -2-hydroxypropyl-.beta.-cyclodextrin (HPBCD), povidone, (polyvinyl pyrrolidone, PVP homopolymer), hypromellose (hydroxypropylmethylcellulose, HPMC), polymethacrylates (poly(methacrylic acid, methyl methacrylate 1:1; poly(methacrylic acid, ethyl acrylate) 1:1), hydroxypropyl cellulose (HPC), and cellulose acetate phthalate (CAP) and mixtures thereof. Preferably used high viscosity polymers are Hypromellose K15MCR, Hypromellose K4MCR or mixtures thereof.
The term “Less Sedation” as used in the context of the present specification is defined as a depressed level of consciousness but the ability to independently and continuously maintain a patient airway and respond appropriately to physical stimulation is retained.
The term “Sustained release” as used in the context of the present specification is defined as release of a pharmaceutical agent in a continuous manner over a prolonged period of time.
By “prolonged period of time” it is meant a continuous period of time of greater than about 1 hour, preferably, greater than about 4 hours, more preferably, greater than about 8 hours, more preferably greater than about 12 hours, more preferably still, greater than about 16 hours up to more than about 24 hours.
The term “immediate release” as used herein refers to immediate release of drug from the compositions after administration. This term is also used by the pharmacopoeias and the FDA. Immediate release dosage forms are designed to give a fast onset of drug action
As used herein, unless otherwise noted, “rate of release” or “release rate” of a drug refers to the quantity of drug released from a dosage form per unit time, e.g., milligrams of drug released per hour (mg/hr) or a percentage of a total drug dose released per hour. Drug release rates for dosage forms are typically measured as an in vitro rate of drug release, i.e., a quantity of drug released from the dosage form per unit time measured under appropriate conditions and in a suitable fluid. The time at which a specified percentage of the drug within a dosage form has been released from the dosage form is referred to as the “T.sub.x” value, where “x” is the percent of drug that has been released.
“C” denotes the concentration of drug in blood plasma, or serum, of a subject, and is generally expressed as mass per unit volume, for example nanograms per milliliter. For convenience, this concentration may be referred to herein as “drug plasma concentration”, “plasma drug concentration” or “plasma concentration” which is intended to be inclusive of a drug concentration measured in any appropriate body fluid or tissue. The plasma drug concentration at any time following drug administration is referenced as Ctime, as in C9 hr or C4 hr, etc.
The maximum plasma drug concentration during the dosing period is referenced as Cmax, while Cmin refers to the minimum blood plasma drug concentration at the end of a dosing interval; and Cave refers to an average concentration during the dosing interval.
The term “bioavailability” refers to an extent to which—and sometimes rate at which—the active moiety (drug or metabolite) enters systemic circulation, thereby gaining access to the site of action.
“AUC” is the area under the plasma concentration-time curve and is considered to be the most reliable measure of bioavailability. It is directly proportional to the total amount of unchanged drug that reaches the systemic circulation.
The concentration of high viscosity polymers used in the present invention alone ranges from 1% to 40% (w/w) to the total concentration. Preferably used concentration of high viscosity polymers is from 1.00 to 20% (w/w).
The Hydroxyzine Hydrochloride SR tablets developed using direct compression method experienced sticking of blend to tablet punch was observed during compression. Even after addition of anti-sticking agent like talc, glyceryl monostearates, calcium stearate, magnesium stearate, stearic acid, glyceryl behenate, and polyethylene glycol, DiCOM DC SR (Co-processed excipient system for direct compression). Segregation of blend was observed along with punch stickiness during compression.
Further to avoid the problem of punch sticking different excipients were tried like spray dried lactose/ Anhydrous Lactose, pregelatinized starch were used in the formula composition to improve the manufacturing process. A combination of Hydroxypropylmethyl cellulose (HPMCK15MCR and HPMCK4MCR) were used to attain a target dissolution profile.
With intent of generating a stable sustained release formulation, two dissolution profiles with 12 hr and 16hr dissolution profiles were targeted to achieve the desired target. Polymer quantities were used at a ratio of 15 to 30% w/w, preferably 17.5%w/w and 25%w/w in core tablet formulations. Hydroxypropyl cellulose is used as a binder for granulation. The dried granules were mixed with colloidal silica and Magnesium stearate and compressed. The core tablets were coated with a barrier coating (Ethyl cellulose and Hydroxypropyl cellulose combination) in coating machine followed by film coating using Opadry AMB white.
Formula with higher polymer quantity and with High viscous polymer (HPMCK15MCR), the desired dissolution profile completed in 16hr.
On the basis of development trials, the percentage of polymer (A combination of HPMC K15MCR and HPMC K4MCR) at 10 to 30% w/w, preferably 12%, Preferably 15%, preferably 17.5%, preferably 20%, preferably 25%, preferably 30% w/w of core tablet, followed by barrier coating with Ethyl cellulose and HPC in a ratio of 65:35 at a weight gain of 3%w/w over core tablets was found to be an ideal composition to control the drug release profile. More preferably polymer at 17.5%, w/w of core tablet is found to be more suitable.
Suitable diluent, may be selected from, but not limited to the group consisting of microcrystalline cellulose, lactose monohydrate, sucrose, fructose, glucose dextrose, or other sugars, dibasic calcium phosphate, calcium sulfate, cellulose, ethylcellulose, cellulose derivatives, kaolin, mannitol, lactitol, maltitol, xylitol, sorbitol, or other sugar alcohols, dry starch, saccharides, dextrin, maltodextrin or other polysaccharides, inositol or mixtures thereof. Preferably used diluent is Lactose monohydrate.
The concentration of diluent used in the present invention ranges from 20% to 70% (w/w) to the total concentration, most preferably 35 to 55 % (w/w).
Suitable binder may be selected from, but not limited to the group consisting of polyvinylpyrrolidone (PVP), copovidone, hydroxypropyl cellulose (Klucel EXF), hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methylcellulose, and combinations thereof. Preferably used binder is Hydroxypropyl cellulose.
The concentration of binder used in the present invention ranges from 0.05% to 10% (w/w) to the total concentration, most preferably 1 to 4.5% (w/w).
Suitable glidant, may be selected from, but not limited to the group consisting of porous silica, colloidal silicon dioxide, cellulose, calcium phosphate, di or tri-basic and the like. Preferably used glidant is porous silica.
The concentration of glidant used in the present invention ranges from 0.05% to 5% (w/w) to the total concentration, most preferably 1 to 3% (w/w).
Suitable lubricant includes, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, sodium lauryl sulfate, glyceryl palmitostearate, and any combination thereof. Preferably used lubricant magnesium stearate.
The concentration of lubricant used in the present invention ranges from 0.01% to 5% (w/w) to the total concentration, most preferably 0.05 to 5% (w/w).
Suitable water-insoluble release modifier may be selected from, but not limited to the group consisting of polyvinyl acetate, polyvinyl chloride, polyvinyl carbonate, ethyl cellulose, nitrocellulose, vinylidene chloride-acrylonitrile copolymer, acrylonitrile-styrene copolymer, ethylene vinyl acetate, cellulose acetate, cellulose acetate phthalate, cellulose acetate butyrate, copolymers of vinyl pyrrolidone, blend of polymers comprising polyvinyl acetate, hydroxypropylmethylcellulose phthalate, methacrylic acid copolymers such as Eudragit® LI00/SI00/LI00-55 and the like or mixtures thereof; methacrylate copolymers such as Eudragit® E100/EPO, Eudragit® RL100/RL30D/RLPO, Eudragit® RS100/RS30D/RSPO and the like or mixtures thereof. Preferably used water-insoluble release modifier is ethyl cellulose.
The concentration of water-insoluble release modifier used in barrier of present invention ranges from 0.05% to 10% to the total concentration, most preferably 1 to 5% (w/w).
Pore forming agent hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, glycerol, propylene glycol, polyethylene glycol, sucrose, mannitol, lactose, sodium chloride or a combination thereof. Preferably used pore forming agent is Hydroxypropyl cellulose.
The concentration of pore forming agent used in the present invention ranges from 0.05% to 10% (w/w) to the total concentration, most preferably 1 to 5% (w/w)
Film coating used in the present invention is preferably opadry film coating, hydroxypropyl cellulose, hypromellose, eudragit coating agents, most preferably Opadry AMB II white and Opadry AMB.
The concentration of opadry film coating used in the present invention ranges from 0.1% to 5% (w/w) to the total concentration, most preferably 2 to 5% (w/w).
During stability of samples, immediate dissolution was observed. In order to address the issue of fastness in dissolution profile during stability, trials were executed with binder(s) (to create a binding force between the particles), water insoluble diluents like microcrystalline cellulose, pregelatinized starch (which acts as binder and gives additional strength to tablets) and by increasing the polymer content in formulation. Inspite of all these trials to match the target dissolution profile, during stability, the dissolution profile became faster in all trial batches. In order to make a stable formulation, wet granulation was opted to make stronger granules, followed by barrier coating with ethyl cellulose and film coating with Opadry AMB white.
The pharmaceutical composition of the present specification is stable throughout the shelf life when the compositions is subjected to accelerated and long-term stability studies.
The following examples will further describe certain specific aspects and embodiments of the invention in greater details and are not intended to limit the scope of invention
EXAMPLES
Example 1:
Sr. No. Name of Ingredients Ex 1a Ex 1b Ex 1c Ex 1d Ex 1e Ex 1f

%w/w %w/w %w/w %w/w %w/w %w/w
Core matrix
1. Hydroxyzine Hydrochloride 24.37 23.56 27.67 26.98 23.56 23.68
2. Lactose monohydrate 50.2 48.54 42.43 47.61 50.09 36.84
3. Hypromellose 14.63 16.49 16.64 14.27 14.15 18.41
4. Hydroxypropyl cellulose 2.44 2.35 2.21 1.9 2.36 4.21
5. Porous silica 1.46 1.41 1.84 1.87 1.41 2.63
6. Magnesium stearate 0.97 1.88 1.84 1.36 1.89 4.21
7. Isopropyl alcohol QS QS QS QS QS QS
8. Purified water QS QS QS QS QS QS
Barrier coating
9. Ethyl cellulose 1.46 1.83 1.84 2.22 1.41 3.19
10. Hydroxypropyl cellulose 1.46 1.03 1.84 1.26 1.41 3.68
11. Isopropyl alcohol QS QS QS QS QS QS
12. Acetone QS QS QS QS QS QS
Film coating
13. Opadry AMB II 3.01 2.91 3.69 2.53 2.91 3.15
14. Purified water QS QS QS QS QS QS
Total 100 100 100 100 100 100

Process for preparing Tablets:
a. Hydroxyzine hydrochloride, hypromellose, Lactose monohydrate and hydroxypropyl cellulose were mixed as per the quantities given in Example 1.
b. Co-sifted the mixture and was transferred into rapid mixer granulator (RMG), obtain suitable dried granules, isopropyl alcohol and purified water mixture was added and were dried in Fluid bed processor
c. The dried granules were milled and Porous silica mixed and blended
d. Magnesium stearate was added and compressed using suitable punch toolings in compression machine.
e. The blend of step d was coated with barrier coating and finally film coated.

Stability Study:
The stability of the compositions prepared as per example 1e was evaluated through accelerated stability studies. The composition prepared according to the formula and process of example 1e was subjected to stability study at 30°C/75% RH and 40 °C/75% RH. The compositions were found to be stable at accelerated conditions. Table 1 and Table 2 represents the study result data.
Table 1: Stability Data of Hydroxyzine hydrochloride sustained release tablet of the present invention according to Example 1 (Storage Condition: 30°C/75% RH)

S.No Characteristic Specification 3 Months 6 Months
1. Description White to off white, oval shaped film coated tablets plain on both sides White, oval shaped film coated tablets plain on both sides White, oval shaped film coated tablets plain on both sides
2. Assay NLT 90.0% and NMT 110.0% of the labelled amount 98.90 98.21
3. Dissolution NMT 35% dissolved in 1 hour 16 (14) 15 (4.7)
Between 40% and 85% in 4 hours 55 (7.2) 57 (4.8)
NLT 85% dissolved in 10 hr 94 (3.9) 100 (3.4)
4. Related Substances Single maximum individual impurity:
Not more than 0.2% 0.09 0.08
Total impurities:
Not more than 0.50% 0.16 0.15
5. Water content Not more than 7.0% w/w 4.20 4.02
Table 2: Stability Data of Hydroxyzine hydrochloride sustained release tablet of the present invention according to Example 1 (Storage Condition: 40°C/75% RH)

S.No Characteristic Specification 3 Months 6 Months
1. Description White to off white, oval shaped film coated tablets plain on both sides White, oval shaped film coated tablets plain on both sides White, oval shaped film coated tablets plain on both sides
2. Assay NLT 90.0% and NMT 110.0% of the labelled amount 98.45 99.21
3. Dissolution NMT 35% dissolved in 1 hour 15 (5.5) 17 (3.1)
Between 40% and 85% in 4 hours 54 (5.7) 65 (5.0)
NLT 85% dissolved in 10 hr 94 (1.9) 91 (4.5)
4. Related Substances Single maximum individual impurity:
Not more than 0.2% 0.09 0.08
Total impurities:
Not more than 0.50% 0.16 0.14
5. Water content Not more than 7.0% w/w 4.03 4.11

From the above comparison formulation according to Example 1e at storage conditions 30°C/75% RH and 40°C/75% RH are complied with the specification limits.
Comparative Bioequivalence Study with Blunt Cmax:
A Randomized, Open Label, Balanced, Two Treatment, Two Period, Two Sequence, Single Dose, Crossover, Comparative Bioavailability Study of Hydroxyzine Sustained Release Tablet of the present invention., Comparing with two tablets of Atarax® 25 mg Dr. Reddy’s Laboratories Limited, in Normal Healthy Adult Human Subjects Under Fasting Conditions.
Table 3: BE study results
Geometric Least Square Means Cmax
(ng/mL) AUC0-t (ng*hr/mL) AUC0-inf (ng*hr/mL)
Test (T) 55.9417 1309.2720 1189.0979
Reference (R) 87.7016 1378.0374 1290.4627

The Ratio, 90% confidence intervals and intra subject variability of ln-transformed
pharmacokinetic parameters are summarized below:
Table 4: Ratios, Intra Subject Variability and 90% CI for Hydroxyzine (N=70):
Parameters T/R Ratio (%)
(90% Confidence Interval) BIOEQUIV with respect to AUC Intra CV (%) Power (%)
AUC0-
inf(ng*hr/mL) 95.01 (87.20,103.51 ) YES 31.1284 99.5303
AUC0-t (ng*hr/mL) 92.15 (81.75,103.86 ) YES
44.4558 92.2917

Efficacy Results:
The 90% confidence intervals of geometric least square mean ratio of ln-transformed pharmacokinetic parameters AUC0-t and AUC0-inf between test and reference products falls within the range of 80.00% to 125.00% for Hydroxyzine. Therefore, the compositions of the present invention were found to be efficacious with less sedative effect i.e the test formulation is having blunt Cmax compared to the reference.

Safety Results:
Safety assessments of the compositions of the present invention were based on a medical
review of adverse events (AEs), physical examination, recording of vital signs and clinical laboratory tests. The compositions of the Example 1 were well tolerated and was found to be safe.
Table 5: Mean Concentration of test (T) and reference (R) products for Hydroxyzine
under fasting condition:
Time (hr) Mean Conc. (ng/ml)
Test
Atarax (Sustained Release) Reference
Atarax (Immediate release)
0.00 0.077 0.042
1.00 2.259 38.010
2.00 18.240 70.115
6.00 58.344 58.276
12.00 41.517 34.688
36.00 14.580 12.065

From the above results, it clearly states that Onset on action of both test SR formulation and reference IR formulation were similar, however the test SR formulation has shown steady and consistent increase in concentration vowing to lesser adverse effects like sedation and also the test SR formulation Cmax was steadily increasing in ascending order and the maximum concentration is observed at 6.0 hr but in reference IR formulation the maximum concentration was observed at 2.5 hrs post dose which shows that the formulation of present invention has benefit of avoiding sedation as side effect.

Table 6: Comparison of Sedative effect in enrolled subjects:
Atarax SR 50mg (Test) Atarax IR 50 mg (2X25mg) - Reference
Only 5 out of 70 subjects (~7% only) are
showing mean value of concentration more
than desired concentration between 1 to 6 hrs post dose. 54 out of 70 subjects (~77%) are showing
mean value of concentration more than
desired concentration between 1 to 6 hrs post dose

From above results of Table 6 it was found that only ~7% subjects treated with experienced sedation compared to the ~77% subjects when treated with reference formulation, which shows that the test formulation is less sedative compared to reference formulation by almost 10times.
,CLAIMS:We Claim:
1. An oral pharmaceutical composition comprising Hydroxyzine, or its pharmaceutically acceptable salts as active ingredient along with other pharmaceutically acceptable excipients, with less sedation,
wherein the pharmaceutically acceptable excipients are selected from high viscosity polymers, diluents, binder, filler, glidant, water-insoluble release modifier, pore forming agent, lubricant, solvents

2. The composition as claimed in claim 1, wherein the composition is tablets, capsules, mini-tablets, granules.
3. The composition as claimed in claim 1, wherein the composition is a sustained release dosage form comprising Hydroxyzine, or a pharmaceutically acceptable salt as active ingredient and pharmaceutically acceptable excipients.
4. A sustained release oral dosage form of hydroxyzine, or its pharmaceutically acceptable salts, comprising a) core matrix, b) a barrier coating surrounding the core and c) an outer film coating.
5. The sustained release oral dosage form as claimed in claim 5, wherein the dosage form comprises
a) a core matrix comprising the active ingredient and one or more high viscosity polymers;
b) a barrier coating comprising atleast one water-insoluble release modifier and a pore forming agent; and
c)a film coating.
6. The sustained release oral dosage form as claimed in claim 5, wherein Hydroxyzine, or its pharmaceutically active salt comprise 20% to 60% (w/w) of the core matrix.
7. The sustained release oral dosage form as claimed in claim 6, wherein one or more high viscosity polymers in the core matrix is selected from the group consisting of HPMC polymers, copovidone, hypromellose phthalate, hypromellose acetate succinate, -2-hydroxypropyl-.beta.-cyclodextrin (HPBCD), povidone, polymethacrylates, hydroxypropyl cellulose (HPC), and cellulose acetate phthalate (CAP) and mixtures thereof.
8. The sustained release oral dosage form as claimed in claim 6, wherein barrier coating comprises ethyl cellulose, polyvinyl acetate, polyvinyl chloride as water-insoluble release modifier, Hydroxypropyl cellulose, glycerol, propylene glycol or mixture thereof as pore forming agent
9. The sustained release oral dosage form as claimed in claim 6, is targeted to release the drug with blunted Cmax with plasma concentration values ranging between 40±12 ng/mL, and has low sedative effect.
10. A method of preparing of composition of claim 5, where in the method comprises:
(a) sifting and mixing hydroxyzine with pharmaceutically active ingredients,
(b) dry mixing the granules of step (a) and adding the mixture of solvents
(c) drying the wet granules, milling and sifting followed by blending and lubricating with lubricant
(f) compressing the lubricated blend followed by barrier coating and film coating
11. The composition of claim 5, wherein composition when subjected to in vitro changeover dissolution study exhibits following release profile:
i) releases not more than 35% in 1 hour,
ii) releases at least about 40% - 85% in 4 hours and not less than 85% in 10 hours, in 900 ml of pH 6.8 phosphate buffer medium at 50 rpm and 37°C using USP type II apparatus.
12. The sustained release oral dosage form as claimed in claim 5, wherein the dosage form is a tablet capsule, mini-tablet, or granules.