Technical field of invention
The technical field of the present invention relates to pharmaceutical dosage form of pseudoephedrine and loratadine for twice-a-day administration comprising an extended release core of pseudoephedrine and immediate release coating layer of loratadine and pseudoephedrine. It also relates to dosage forms providing an in vitro release profile of pseudoephedrine, which is pH independent and devoid of any lag phase.
BACKGROUND OF THE INVENTION
Loratadine is a non-sedating long acting antihistamine useful, for example, in alleviation of seasonal allergic rhinitis symptoms such as sneezing and itching. On the other hand pseudoephedrine and its pharmaceutically acceptable salts such as hydrochloride or sulphate are well recognized by those skilled in the art as safe and effective nasal decongestants. Combining decongestants and antihistamines have shown to offer better relief from symptoms of rhinitis than therapy involving use of the drugs individually.
Loratadine due to its long half life needs to be administered once or twice per day, whereas pseudoephedrine having short half life is commonly administered three or four times a day. Administration of multiple doses per day is extremely cumbersome and extended release dosage forms, which reduce the frequency of dosage administration, are highly desirable.
Extended release dosage forms of the long acting loratadine and short acting pseudoephedrine should preferably be so designed that loratadine is released in a conventional manner whereas release of pseudoephedrine is extended over a desired period of time. Few of such extended release dosage forms are known in the art.
For example, U.S. Pat. No. 4,996,061 assigned to Merrell Dow Pharmaceuticals discloses a pharmaceutical composition in the form of a multiple-compression tablet
comprising of two discrete zones. The first discrete zone is made with formulation (A) comprising a therapeutically effective decongestant amount of a sympathomimetic drug, and the second discrete zone is made with formulation (B) comprising a therapeutically effective antihistaminic amount of a piperidinoalkanol.
U.S. Pat. No. 5,314,697 assigned to Schering Corporation discloses tablets that contain core comprising decongestant pseudoephedrine, which is released over an extended period and a film coating surrounding the core comprising a non-sedating antihistamine loratadine for immediate release. The tablets disclosed here are relatively bigger comprising less than 30% of pseudoephedrine in the core.
U.S. Pat. No. 6,267,986 assigned to Ranbaxy Laboratories Limited discloses an oral controlled release pharmaceutical composition in the form of a tablet comprising pseudoephedrine or its pharmaceutically acceptable salts and a long acting antihistamine or their pharmaceutically acceptable salts, wherein loratidine is released at a rapid rate, and pseudoephedrine or its pharmaceutically acceptable salt is released at a controlled rate unaffected by the varying pH of the gastrointestinal tract.
Commercially, extended release tablets of pseudoephedrine and loratadine are marketed by Schering under the tradename of Claritin D® 24 hour ER and Claritin D® 12 hour ER. Claritin D® 24 hour ER tablet contains 10 mg loratadine and 240 mg pseudoephedrine hydrochloride and is recommended for once-daily administration. Claritin D® 12 hour ER tablet contains 5 mg loratadine and 120 mg pseudoephedrine hydrochloride and is recommended for twice-daily administration.
Commercially available pseudoephedrine and loratidine compression coated Claritin D® 12 hour ER tablets have a typical in-vitro drug release profile of pseudoephedrine showing immediate release phase within 1 hour, followed by a 'no release phase' of 1-3 hours commonly referred to as lag phase, and a pH dependent extended release phase of about 5-6 hours. Presence of a substantial lag phase in the release profile appears to be a characteristic prerequisite for obtaining a bioequivalent dosage form. Further,
fabrication of dosage forms with reproducing lag phase demands skillful selection of specific excipients and complex manufacturing techniques.
We have now surprisingly developed an alternative approach to prepare bioequivalent pharmaceutical dosage form of pseudoepedrine and loratidine having a in vitro release profile, which is pH independent and also devoid of the characteristic lag phase.
Summary of the Invention
In one of the aspect it provides, a pharmaceutical dosage form of pseudoephedrine and loratidine for twice-a-day administration comprising:
(1) An extended release core comprising a portion of pseudoephedrine, hydrophilic polymer(s), salt of polyuronic acid; pharmaceutically acceptable salt of group II metal ion; and
(2) An immediate release layer comprising the remaining portion of pseudoephedrine, and loratadine;
wherein the dosage form is characterized by a in vitro release profile of pseudoephedrine which is pH independent and devoid of any lag phase.
In another aspect it provides, a pharmaceutical dosage form of pseudoephedrine and loratadine for twice-a-day administration comprising:
(1) An extended release core comprising a portion of pseudoephedrine, hydrophilic polymer(s), salt of polyuronic acid, pharmaceutically acceptable salt of group II metal ion;
(2) An immediate release layer comprising the remaining portion of pseudoephedrine, and loratadine; and
(3) One or more additional layers comprising film-forming polymers, between the core and immediate release layer and/or above the immediate release layer;
wherein the dosage form is characterized by a in vitro release profile of pseudoephedrine which is pH independent and devoid of any lag phase.
In another aspect it provides, a pharmaceutical dosage form of pseudoephedrine and loratadine for twice-a-day administration comprising:
(1) An extended release core comprising a portion of pseudoephedrine constituting about 35% to about 50% w/w of core, hydrophilic polymer(s), salt of polyuronic acid; pharmaceutically acceptable salt of group II metal ion; and
(2) An immediate release layer comprising the remaining portion of pseudoephedrine and loratadine;
wherein the dosage form is characterized by a in vitro release profile of pseudoephedrine which is pH independent and devoid of any lag phase.
In another aspect it provides, a pharmaceutical dosage form of pseudoephedrine and loratadine for twice-a-day administration comprising:
(1) An extended release core comprising a portion of pseudoephedrine, hydrophilic polymer(s), salt of polyuronic acid; pharmaceutically acceptable salt of group II metal ion; and
(2) An immediate release layer comprising the remaining portion of pseudoephedrine, and loratadine;
wherein the dosage form is characterized by a in vitro release profile of pseudoephedrine which is pH independent and devoid of any lag phase, and is as follows:
(a) not less than 35% in 1 hour,
(b) about 55% to about 80% in 3 hours, and
(c) more than 85% in 6 hours.
In another aspect it provides, a pharmaceutical dosage form of pseudoephedrine and loratadine for twice-a-day administration comprising:
(1)An extended release core comprising about a portion of pseudoephedrine constituting about 35% to about 50% w/w of core, hydrophilic polymer(s), salt of polyuronic acid, pharmaceutically acceptable salt of group II metal ion; and (2) An immediate release layer comprising the remaining portion of pseudoephedrine, and loratadine;
wherein the dosage form is characterized by a in vitro release profile of pseudoephedrine which is pH independent and is devoid of any lag phase, and is as follows:
(a) not less than 35% in 1 hour;
(b) about 55% to about 80% in 3 hours; and
(c) more than 85% in 6 hours.
In another aspect there is provided, a process for the preparation of a pharmaceutical dosage form of pseudoephedrine and loratadine for twice-a-day administration comprising the steps of:
(a) blending a portion of pseudoephedrine with one or more intragranular excipients;
(b) granulating the blend;
(c) blending the granules with hydrophilic polymer(s), salt of polyuronic acid, pharmaceutical^ acceptable salt of a group II metal ion and other extragranular excipients;
(d) compressing the blend to form extended release core;
(e) preparing a coating composition comprising remaining portion of pseudoephedrine, loratadine and other pharmaceutical excipients; and
(f) applying the coating composition as immediate release layer over the extended release core;
wherein the dosage form is characterized by a in vitro release profile of pseudoephedrine which is pH independent and devoid of any lag phase.
In another aspect there is provided, a process for the preparation of a pharmaceutical dosage form of pseudoephedrine and loratadine for twice-a-day administration comprising the steps of:
(a) blending a portion of pseudoephedrine with hydrophilic polymer(s), salt of polyuronic acid, pharmaceutically acceptable salt of a group II metal ion and other pharmaceutical excipients;
(b) compressing the blend to form extended release core;
(c) preparing a coating composition comprising remaining portion of pseudoephedrine, loratadine and other pharmaceutical excipients; and
(d) applying the coating composition as immediate release layer over the extended release core;
wherein the dosage form is characterized by a in vitro release profile of pseudoephedrine which is pH independent and devoid of any lag phase.
In another aspect it provides, a method of treating rhinitis in human by administering to the human in need thereof, a pharmaceutical dosage form of pseudoephedrine and loratadine for twice-a-day administration comprising:
(1) An extended release core comprising a portion of pseudoephedrine, hydrophilic polymer(s), salt of polyuronic acid; pharmaceutically acceptable salt of a group II metal ion; and
(2) An immediate release layer comprising the remaining portion of pseudoephedrine, and loratadine;
wherein the dosage form is characterized by a in vitro release profile of pseudoephedrine which is pH independent and devoid of any lag phase.
In another aspect it provides, a pharmaceutical dosage form of pseudoephedrine and loratadine for twice-a-day administration in combination with one or more additional drug(s), such as an analgesic.
In yet another aspect it provides, a bioequivalent dosage form to the commercially available Claritin D® 12 hour ER tablet of Schering.
The details of one or more embodiments are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and claims.
Detailed Description of the Invention
The present invention is not limited to particular process steps and materials disclosed herein, but are extended to equivalents thereof as would be recognized by those ordinarily skilled in the relevant art. It should also be understood that terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting.
The term "bioequivalent" as used herein refers to extended release dosage forms of pseudoephedrine and loratidine (Test), pharmacokinetic parameters of which on comparison with commercially available Claritin D® 12 hour (Reference) qualify the FDA limits set for bioequivalence.
The term 'no release phase' or 'lag phase' as used herein refers to initiation of release of pseudoephedrine from extended release matrix core in more than an hour after release of pseudoephedrine from immediate release layer.
Claritin-D® 12 hours ER tablet is a compression coated oral dosage form of pseudoephedrine and loratidine, available in the market. It has an immediate release core comprising pseudoephedrine which is compression coated with a pH dependent dibasic calcium phosphate layer to form the extended release core tablet. The core tablet is further coated with an immediate release layer comprising immediate release portion of pseudoephedrine and loratidine. The in vitro release profile in 900 ml dissolution media (0.1N HCI for 1 hour followed by pH 6.8 phosphate buffer) in USP-1 apparatus at 75 rpm shows an initial burst release of about immediate release portion of pseudoephedrine and loratidine, followed by a pH dependent lag phase of 1-3 hours. The lag phase is terminated by the initiation of release of extended release portion of pseudoephedrine from the core. The lag phase observed is mainly attributed to the compression coating of dibasic calcium phosphate. The characteristic lag phase in the in vitro release profile of Claritin D® 12 hour ER tablet appears to be a important for in vivo performance, and one of the prerequisites for development of bioequivalent dosage forms. A pH dependent coating comprising dibasic calcium phosphate applied using complex compression coating techniques seems mandatory, as our efforts of achieving
the above dissolution profile with a lag phase by including dibasic calcium phosphate in the core matrix failed.
Extended release dosage forms of pseudoephedrine and loratadine of the present invention minimizes the above complexities by using lower amounts of excipients in the extended release matrix core, yet being bioequivalent to Claritin D® 12 hour. The dosage forms are manufactured using simple conventional tableting and coating techniques, avoiding the extra complex pH dependent compression coating necessary for providing the characteristic lag phase. The in vitro release profile of the pharmaceutical dosage forms thus developed is pH independent and is devoid of any lag phase. The absence of 'lag phase' or 'no release phase' is mainly attributed to the use of hydrophilic polymers having high affinity for water, water thus penetrates into the polymer matrix and dissolve it to form aqueous channels through which pseudoephedrine diffuses out. The bioequivalent dosage form consequently developed is easy to prepare using simple techniques and is cost effective. Additionally, due to the minimal use of the excipients, small dosage form having reduced total weight is obtained.
The term 'pseudoephedrine' as used herein includes free pseudoephedrine base and its pharmaceutical^ acceptable acid addition salts, hydrates or mixtures thereof. In particular, pseudoephedrine sulphate is used. The extended release dosage form may comprise 80 to 160 mg of pseudoephedrine, in particular 120mg. The total dose of pseudoephedrine may be distributed in the extended release core and immediate release layer in the ration of about 10:1 to about 3:1, in particular 5:1. Extended release portion of pseudoephedrine may comprise from about 35% to about 60% w/w of the core, in particular about 40% to about 50% w/w of the core.
The term 'loratidine' as used herein includes free loratidine base and its pharmaceutically acceptable acid addition salts, hydrates or mixtures thereof. In particular, loratidine as free base is used. Loratadine is a long acting histamine and the dosage form may comprise the complete dose for immediate release in the immediate
release layer. The loratadine dose may vary from about 4 to about 6 mg, in particular 5 mg.
Examples of 'hydrophilic polymer' may include cellulose ethers such as hydroxypropyl methylcellulose, hydroxypropylcellulose, sodium carboxymethyl cellulose and the like; gums such as xanthan gum, acacia, tragacanth gum, guar gum, karaya gum; polyacrylate polymers such as homopolymers based on acrylic acid crosslinked with allyl sucrose or allyl pentaerythritol, or copolymer based on acrylic acid and long chain (C10 -C30) alkyl acrylates and cross-linked with allylpentaerythritol and the like; alginates; gelatin; albumin, and the like. The hydrophilic polymers may be present in extended release matrix core in an amount from about 5% to about 50%, in particular from about 12% to about 30% w/w of core.
In particular, the hydrophilic polymer is hydroxypropyl methylcellulose, hydroxypropylcellulose, or mixture thereof. Examples of hydroxypropyl methylcellulose polymers include those available commercially from Dow Chemical Co. under the brand name Methocel, such as, Methocel K4M, Methocel K15M, Methocel K100M, Methocel K4MCR, Methocel K15MCR, MethocelKIOOMCR, and the like. Hydroxypropylcellulose polymers that may be used include those available commercially under the brand names such as Klucel™ and HPC™ from Aqualon and Nippon Soda Co.
Examples of salt of polyuronic acid may include both water soluble and water insoluble salt of polyuronic acid such as alginic acid, pectic acid, and the like. Examples of water insoluble salts include salts of polyuronic acid with metal ions such as magnesium, calcium, and the like. Examples of water-soluble salts include salts of polyuronic acid with alkali metals such as sodium, potassium; ammonia ; and the like. In particular, salt of polyuronic acid used is sodium alginate available from Merck & Co., KELCO Division under the trademark KELTONE® such as KELTONE® LVCR and KELTONE® HVCR. A mixture of the same or different viscosity grades of alginic acid salts may be used. An example of a complex salt of a polyuronic acid that may also be used is sodium calcium alginate. The salt of polyuronic acid may be present in an amount from about 4% to about 40%, preferably from about 8% to about 20% w/w of the core.
Examples of pharmaceutically acceptable salt of a group II metal ion include chlorides, carbonates, sulphates salts of calcium, magnesium and the like. Particularly carbonates such as calcium or magnesium carbonate may be used. The pharmaceutically acceptable group II metal ion salt may be used in an amount from about 1% to about 20%, preferably from about 2% to about 10% w/w of the core.
The term "pharmaceutically acceptable excipients" as used herein includes all physiologically inert excipients used in the art for the preparation of pharmaceutical dosage forms and suitable for human consumptions in the amounts employed. Examples include binders, diluents, fillers, glidants/ lubricants stabilizing agents, surfactants, colors, film forming polymers, plasticizers, opacifiers, and the like. The excipients may be used intragranularly, extragranulalry, or in the coating layers.
Examples of 'Binders' include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, and the like.
Examples of 'Fillers' include calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, dextrins, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, sugar compressible, and sugar confectioners, and the like.
Examples of 'Lubricants' or 'Glidants' include talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, magnesium carbonate, magnesium oxide, calcium silicate, starches, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, sodium laurylsulfate, sodium stearyl fumarate, and hydrogenated vegetable oils, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.
Examples of 'Stabilizing agents' include antioxidants, buffer, acids, bases, and the like.
Examples of 'Surfactants' include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in sweetener compositions. These include polyethoxylated fatty acids and its derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterification products, for example polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides for example glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether, polyethylene glycol - 10 -100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene -polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, and palmitoyl carnitine.
The coloring agents include any FDA approved colors for oral use.
Examples of film-forming polymers include cellulose derivatives such as ethylcellulose,
hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose,
carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, partially hydrolyzed polyvinyl alcohol, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit ® RL and RS; and the like. In particular, coating may be a Non-aqueous film coat and/ or a moisture barrier coat. Nonaqueous film coat comprises hydroxy propyl methylcellulose (HPMC), titanium dioxide, polyethylene glycol, talc and a suitable approved color. Aqueous moisture barrier coat comprises partially hydrolysed polyvinyl alcohol, titanium dioxide, talc, soya lecithin, xanthan gum, and a suitable approved color. Alternatively, commercially available
coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used for coating.
Examples of the various 'plasticizers' include glycerin, sorbitol, maltose, glucose, maltitose, sucrose, xylitol, mannitol, erythritol, polyethylene glycols (molecular weight 400-6000), and the like.
Examples of 'opacifiers' include titanium dioxide and/or iron oxides and the like. The opacifiers may be present in an amount of 0.2 to 0.5% w/w.
The term 'dosage form' as used herein includes conventional solid dosage forms for oral administration such as tablets, capsules, pills, granules, and the like. In particular, the solid dosage form is tablet.
Extended release pharmaceutical dosage form of the present invention may be manufactured using simple conventional techniques of tableting and coating, known in the art.
In one of the embodiments, the pharmaceutical dosage form of pseudoephedrine and loratadine, for twice-a-day administration may be prepared by a process, comprising the following steps:
(a) blending a portion of pseudoephedrine with diluent and binder, and wet granulating the blend with a granulating fluid; or blending a portion of pseudoephedrine with diluent and wet granulating the blend with a solution/dispersion of binder in the granulating fluid;
(b) drying and sizing the granules;
(c) blending with one or more hydrophilic polymer(s), salt of polyuronic acid, pharmaceutically acceptable salt of a group II metal ion, and other pharmaceutical excipients;
(d) compressing the blend into extended release core; and
(e) layering with immediate release coating composition comprising remaining
portion of pseudoephedrine, loratadine, and pharmaceutical excipients.
In another embodiment, the pharmaceutical dosage form of pseudoephedrine and loratadine, for twice-a-day administration may be prepared by a process, comprising the following steps:
(a) blending a portion of pseudoephedrine with diluent and binder;
(b) dry granulating the blend by roller compaction or slugging;
(c) drying and sizing the granules;
(d) blending with one or more hydrophilic polymer(s), salt of polyuronic acid, pharmaceutically acceptable salt of a group II metal ion and pharmaceutical excipients;
(e) compressing the blend into extended release core; and
(f) layering with immediate release coating composition comprising remaining portion of pseudoephedrine, loratadine, and pharmaceutical excipients.
In another embodiment, the pharmaceutical dosage form of pseudoephedrine and loratadine, for twice-a-day administration may be prepared by a process, comprising the following steps:
(a) blending a portion of pseudoephedrine with one or more hydrophilic polymer(s), salt of polyuronic acid, pharmaceutically acceptable salt of a group II metal ion, lubricant, filler, diluent, and binder;
(b) directly compressing into extended release core; and
(g) layering with immediate release coating composition comprising remaining
portion of pseudoephedrine, loratadine, and pharmaceutical excipients.
In another embodiment, the pharmaceutical dosage form of pseudoephedrine and loratadine, for twice-a-day administration may be prepared by a process, comprising the following steps:
(a) blending a portion of pseudoephedrine with one or more hydrophilic polymer(s),
salt of polyuronic acid, pharmaceutically acceptable salt of a group II metal ion,
lubricant, filler, diluent, and binder;
(b) forming a wet mass using a granulating fluid or solution/dispersion of pharmaceutical excipients in granulating fluid;
(c) passing the wet mass through an extruder equipped with a screen, and spheronizing the extrudate in a spheronizer;
(d) compressing the spheroids into extended release core;
(h) layering with immediate release coating composition comprising remaining portion of pseudoephedrine, loratadine and pharmaceutical excipients.
The pharmaceutical dosage forms of pseudoephedrine and loratadine prepared in any of the above embodiments may additionally be coated with one or more non-functional coating layers comprising film-forming polymers. The additional coating layers may be applied in between the two drug layers and/or above the immediate release layer.
The immediate release layer and additional layers may be applied using conventional coating techniques well known in the art such as spray coating in a conventional coating pan, or fluidized bed processor, dip coating, melt coating, and the like. In particular spray coating may be used.
Examples of granulating fluid or solvents for preparing solution/dispersion of coating composition include aqueous or organic solvents, and mixtures thereof; such as water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetone and the like.
In order to further illustrate the present invention and the advantages thereof, the following specific examples are given with the understanding that these examples are intended only to be illustrations without serving as a limitation on the scope of the present invention.
Example 1
Composition of pseudoephedrine and loratadine extended release tablet
Procedure
Pseudoephedrine and loratadine extended using the following steps:
tablets of example I were prepared
(a) Pseudoephedrine, loratadine and pharmaceutical^ acceptable excipients were
sifted to suitable size and required amount were weighed out.
(b) Extended release portion of pseudoephedrine and intragranular portion of
microcrystalline cellulose were blended in rotary mixture granulator.
(c) The blend of step (b) was wet granulated with a solution/dispersion of a portion of povidone in purified water; followed by drying and milling to suitable size.
(d) The granules of step (c) were blended with hydroxypropylmethyl cellulose, sodium alginate, calcium carbonate, extragranular portion of microcrystalline cellulose, remaining portion of povidone, talc, and colloidal silicon dioxide.
(e) The blend of step (d) was compressed into extended release core tablets, using suitable tooling.
(f) Opadry® 02B59025 coating composition was dispersed in purified water.
(g) The extended release core tablets of step (e), were loaded in a spray coater and layered with a portion of opadry® dispersion of step (f) up to a weight gain of about 2%.
(h) Immediate release portion of Pseudoephdrine, and Loratadine were dispersed in
the remaining portion of Opadry® dispersion of step (f). (i) The coating dispersion obtained from step (h) was passed through colloid mill at
zero clearance; (j) The extended release core tablets as obtained from Step (g), were loaded in
spray coater and layered with coating dispersion of step (i) to obtain a weight
gain of 41 mg (17.6%w/w approximately), (k) Opadry® II 30B58700 coating composition was dispersed in purified water. (I) The tablets obtained from step (I) were further coated with an Opadry®
dispersion of step (k).
The tablets of Example 1 thus obtained were studied to in vitro and in vivo studies: I. In vitro dissolution study
Comparative in vitro release of pseudoephedrine from pseudoephedrine and loratadine extended release tablets as per composition of Example 1 and the commercially available Claritin-D® 12 hours ER Tablets were studied using USP I dissolution apparatus, at a basket speed of 75 rpm in 900 ml of (a) 0.1 N HCI for I hour followed by phosphate buffer of pH 6.8 and (b) 0.1 N HCI. The cumulative percentages of pseudoephedrine and loratadine release were analyzed using HPLC at predetermined time intervals. The results of this study are represented in Table 1, Figure 1 and Figure 2.
Table 1. In vitro release of pseudoephedrine sulphate
(Table Removed)
(a) 0.1 N HCI media for I hour followed by phosphate buffer of pH 6.8, (b) 0.1 N HCI media
As evident from Figure 1 the In vitro release of Pseudoephdrine from tablets of example I in different pH media is devoid of any lag phase and is independent of pH variations, which is in contrast to the corresponding pseudoephedrine release from Claritin-D ® 12 hours ER tablets, under the same conditions.
II. In vivo bioequivalence study
The tablets of example 1 (T) were subjected to bioequivalence studies against Claritin-D® 12 hour ER tablets (R) under both non-fasting (fed) and fasted conditions.
The study protocol followed was an open randomized, two treatment, two sequence, two period cross over study in 14 healthy male volunteers with a wash out period of at least 14 days. Blood samples were collected at appropriate time intervals over a period of 48 hours and pseudoephedrine and loratadine content analyzed using a validated in-house HPLC method. Pharmacokinetic parameters Cmax (Maximum plasma concentration), Tmax (Time to attain maximum plasma concentration), AUCo-t (Area under the plasma concentration vs time curve from 0 hours to the time of last sample collected) and AUCo-a (Area under the plasma concentration vs. time curve from 0 hours to infinity) were calculated from the data obtained. Statistical analysis was carried out at 90% interval using "SAS" software package. The results of the study are given in Table 2.
Table 2. Comparative pharmacokinetic data for tablets of example 1 (T) and Claritin-D®

(Table Removed)
The results of bioequivalence studies indicate that extended release tablets of Examplel are bioequivalent to Claritin-D® both with respect to pseudoephedrine and loratadine in fed as well as fasted condition.

WE CLAIM:
1. A pharmaceutical dosage form of pseudoephedrine and loratidine for twice-a-day
administration comprising:
(1) An extended release core comprising a portion of pseudoephedrine, hydrophilic polymer(s), salt of polyuronic acid; pharmaceutically acceptable salt of group II metal ion; and
(2) An immediate release layer comprising the remaining portion of pseudoephedrine, and loratadine;
wherein the dosage form is characterized by a in vitro release profile of pseudoephedrine which is pH independent and devoid of any lag phase.
2. A pharmaceutical dosage form of pseudoephedrine and loratadine for twice-a-day
administration comprising:
(1)An extended release core comprising a portion of pseudoephedrine, hydrophilic polymer(s), salt of polyuronic acid; pharmaceutically acceptable salt of group II metal ion; and (2) An immediate release layer comprising the remaining portion of pseudoephedrine, and loratadine; wherein the dosage form is characterized by a in vitro release profile of pseudoephedrine which is pH independent and devoid of any lag phase, and is as follows:
(a) not less than 35% in 1 hour,
(b) about 55% to about 80% in 3 hours, and
(c) more than 85% in 6 hours.
3. The pharmaceutical dosage form according to claim 1 or 2, wherein pseudoephedrine
is one or more of free pseudoephedrine base, its pharmaceutically acceptable acid
addition salt, or hydrate.
4. The pharmaceutical dosage form according to claim 1 or 2, wherein the weight ratio of pseudoephedrine in the extended release core and the immediate release layer varies from about 10:1 to about 3:1.
5. The pharmaceutical dosage form according to claim 1 or 2, wherein the extended release portion of pseudoephedrine constitutes from about 35% to about 60% w/w of the extended release core.
6. The pharmaceutical dosage form according to claim 1 or 2, wherein loratadine is one or more of free loratadine base, its pharmaceutically acceptable acid addition salt or hydrate.
7. The pharmaceutical dosage form according to claim 1 or 2, wherein hydrophilic polymer is one or more of cellulose ethers, gums, polyacrylate polymers, alginates, gelatin, or albumins.
8. The pharmaceutical dosage form according to claim 1 or 2, wherein salt of polyuronic acid is one or more of alginic acid, or pectic acid.
9. The pharmaceutical dosage form according to claim 1 or 2, wherein pharmaceutically acceptable salt of group II metal ion is one or more of chlorides, carbonates, sulphates salts of calcium, or magnesium.

10. The pharmaceutical dosage form according to claim 1 or 2, wherein the dosage form may further comprise one or more additional layers comprising film-forming polymers, applied in between the core and immediate release layer and/or above the immediate release layer.
11. The pharmaceutical dosage form according to claim 1 or 2, wherein the dosage form may further comprise one or more pharmaceutical excipients selected from
amongst binders, diluents, fillers, glidants/ lubricants, stabilizing agents, surfactants, colors, film- forming polymers, plasticizers, and opacifiers.
12. The pharmaceutical dosage form according to claim 1 or 2, wherein the dosage form further comprises one or more additional drug.
13. The pharmaceutical dosage form according to claim 1 or 2, wherein the dosage form is a solid dosage form selected from amongst tablet, capsule, pill, and granule.
14.The pharmaceutical dosage form of claim 1 or 2 wherein it is bioequivalent to Claritin D® 12 hour ER tablets of Schering.
15. A process for the preparation of a pharmaceutical dosage form of pseudoephedrine
and loratadine for twice-a-day administration comprising the steps of:
(a) blending a portion of pseudoephedrine with one or more intragranular excipients;
(b) granulating the blend;
(c) blending the granules with hydrophilic polymer(s), salt of polyuronic acid, pharmaceutical^ acceptable salt of a group II metal ion and other extragranular excipients;
(d) compressing the blend to form extended release core;
(e) preparing a coating composition comprising loratadine, remaining portion of pseudoephedrine, and other pharmaceutical excipients; and
(f) applying the coating composition as immediate release layer over the extended release core;
wherein the dosage form is characterized by a in vitro release profile of pseudoephedrine which is pH independent and devoid of any lag phase.
16. The process according to claim 15, wherein the blend is granulated using a wet
granulation process or dry granulation process.
17. A process for the preparation of a pharmaceutical dosage form of pseudoephedrine
and loratadine for twice-a-day administration comprising the steps of:
(a) blending a portion of pseudoephedrine with hydrophilic polymer(s), salt of polyuronic acid, pharmaceutically acceptable salt of a group II metal ion and other pharmaceutical excipients;
(b) compressing the blend to form extended release core;
(c) preparing a coating composition comprising loratadine, remaining portion of pseudoephedrine, and other pharmaceutical excipients; and
(d) applying the coating composition as immediate release layer over the extended release core;
wherein the dosage form is characterized by a in vitro release profile of pseudoephedrine which is pH independent and devoid of any lag phase.
18. A method of treating rhinitis in human in need of such treatment, comprising
administering to said human a pharmaceutical dosage form of pseudoephedrine and
loratadine for twice-a-day administration according to claim 1 or 2.
19. A pharmaceutical dosage form of pseudoephedrine and loratadine for twice-a-day
administration and process of its preparation as described and illustrated in the
examples herein.