DESC:FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&

THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
[See section 10, Rule 13]

“A PHARMACEUTICAL MULTI-DRUG DELIVERY COMPOSITION AND METHOD PREPARATION THEREOF”

RAVENBHEL HEALTHCARE PVT. LTD., an Indian Company at: 16-17, EPIP, SIDCO, KARTHOLI, JAMMU KASHMIR -181133, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE NVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The field of the present invention relates generally to medicinal products and, more specifically, to a drug dosage form that enables modulated release of more than one drug upon ingestion by a patient.

BACKGROUND
Oral administration of medicaments such as drugs, supplements, and other nutritional and/or therapeutic agents is typically done with several dosage forms including tablet, or capsules or lozenges etc. A composition may be fabricated from a compressed powder of the medicinal substance. For at least some known ailments, it may be beneficial to administer more than one type of medicament to the patient. As such, composition may be fabricated to enable administration or intake of two or more drugs to the patient in a single dose or single dosage form. At least some known composition include a first drug along with a second drug. However, encapsulating the first drug within the second drug may hinder dissolution of the first drug, and may reduce the dissolution of the first and second drugs. In addition, drugs administered in powder may dissolve at a rate unsuitable for a desired efficacy.

In addition, many known prescription medicines have complicated instructions and dosing regimens. For example, some prescriptions require the oral administration of multiple drug forms containing different types of drugs and/or require administration at different times in the day. Other medicines are to be taken in the morning, afternoon, or evening, some with or without food, some with or without certain types of food, and in particular quantities. As such, it may be difficult for a patient to remember and comply with the administration instructions for a drug or a group of drugs. Failure to comply with such administration instructions can result in suboptimal efficacy.

Peripheral neuropathy is a debilitating condition resulting from nerve damage in the peripheral nervous system. It manifests as sensory disturbances such as burning, tingling, numbness, and sharp, stabbing pain, often accompanied by motor impairments like muscle weakness and loss of coordination. Diabetic peripheral neuropathy (DPN), a common complication of diabetes mellitus, and chemotherapy-induced peripheral neuropathy (CIPN), a side effect of certain anticancer drugs, are among the most prevalent forms of this condition.

The pathophysiology of peripheral neuropathy is complex and multifactorial, involving inflammatory responses, oxidative stress, disrupted neuronal calcium signaling, and impaired neurotransmission. These mechanisms contribute to chronic pain and functional impairments, which significantly reduce the quality of life for affected individuals.

The management of peripheral neuropathy involves pharmacological interventions aimed at alleviating pain and improving nerve function. Several therapeutic agents have been evaluated for symptomatic treatment of neuropathy, which includes anticonvulsants (gabapentin and pregabalin), tricyclic antidepressants (amityptyline and nortyptyline), serotonin-norepinephrine reuptake inhibitors (duloxetine), and analgesics include NSAIDS and some opioids. Some topical treatments like capaicin creams, ketamine and amitriptyline gel, lidocaine patches have also been studied. The options available for the management of neuropathy are prone to debilitating side effects which eventually interfere with the treatment of the subjects and do not improve the life of the patients.

There is a pressing need for novel pharmaceutical compositions and therapeutic strategies that address the limitations of existing therapies.

Hence, there is a direct need in the field of a multi-drug delivery composition wherein the multiple drugs incorporated within said composition do not hamper the dissolution, absorption, and stability of each other. In addition, it is also desired from such formulation that the multiple drugs may have completely different type of release profiles from each other and has good patient compliance.

The present invention seeks to overcome these challenges by developing advanced formulations and combination therapies involving active ingredients to address the unmet needs in treating peripheral neuropathy.

SUMMARY OF THE INVENTION
This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key or essential features.

Accordingly, the present invention provides a multidrug pharmaceutical composition comprising: first active ingredient formulated to exhibit a controlled release profile, wherein the release of the first active ingredient occurs in a sustained and controlled manner over an extended period of time; and a second active ingredient formulated to exhibit a delayed release profile, wherein the release of the second active ingredient delayed for a predetermined period following administration.

In an embodiment of the invention, the first active ingredient being selected from the group of Gabapentin, Duloxetine, Folic acid, Methylcobalamin, Vitamin C, Vitamin B6, Vitamin B3, vitamin Supplements and selective serotonin and norepinephrine reuptake inhibitors (SSNRIS) categories drugs; and wherein the second active ingredient being selected from the group of Gabapentin, Duloxetine, Folic acid, Methylcobalamin, Vitamin C, Vitamin B6, Vitamin B3, vitamin Supplements and Gabapentin, Tiagabine, Pregabalin, etc. drugs.

In an embodiment of the invention, the first active ingredient being formulated with excipients to achieve controlled release of the first active ingredient over a period up to 24 hours.

In an embodiment of the invention, the second active ingredient being formulated with excipients configured to delay the release of the second active ingredient until the composition reaches the small intestine.

In an embodiment of the invention, the controlled release of the first active ingredient being composed of one or more polymers selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and carboxymethyl Cellulose sodium, methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, pregelatinized starch, sodium alginate, gelatin, agar, tragacanth, xanthan gum, guar gum, arab Gum, carrageenan, carboxyvinyl polymer, polyethylene oxide, vinyl acetate povidone polymer matrix, polyvinyl alcohol, polyvinylpyrrolidone, pullulan, sodium polyacrylate, polyoxyethylene, Polyoxypropylene diol.

In an embodiment of the invention, the enteric coating of the second layer being composed of one or more pH-sensitive polymers selected from polyvinyl alcohol acetate phthalate, cellulose acetate phthalate, 1,2,4-benzenetricarboxylic acid acetic acid Cellulose, hydroxypropyl methylcellulose phthalate, 1,2,4-benzenetricarboxylic acid hydroxypropyl methylcellulose, cellulose acetate succinate, hypromellose acetate succinate, hydroxyl acetate Propyl methylcellulose phthalate, methacrylic acid-ethyl acrylate copolymer, methyl vinyl ether-maleic anhydride copolymer, methacrylic acid-ethyl acrylate copolymer aqueous dispersion, methacrylic acid-methacrylate Methyl acrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate copolymer, polyvinyl acetate, ethyl cellulose, polyvinyl acetate and polyvinyl pyrrolidone K30 mixture. It is preferably hypromellose acetate succinate, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methylcellulose phthalate.

In an embodiment of the invention, the pharmaceutical composition being a tablet.

Accordingly, the present invention provides a bilayer tablet comprising a first layer comprises first active ingredient formulated for controlled release, wherein the release of the first active ingredient occurs in a sustained and controlled manner over an extended period of time; and a second layer comprises second active ingredient formulated with an enteric coating to exhibit a delayed release profile, wherein the release of the second active ingredient delayed for a predetermined period following administration; and

In an embodiment of the invention, a first layer comprising first active ingredient being selected from the group of Gabapentin, Duloxetine, Folic acid, Methylcobalamin, Vitamin C, Vitamin B6, Vitamin B3, vitamin Supplements and selective serotonin and norepinephrine reuptake inhibitors (SSNRIS) categories drugs; wherein the second layer comprising second active ingredient being selected from the group of Gabapentin, Duloxetine, Folic acid, Methylcobalamin, Vitamin C, Vitamin B6, Vitamin B3, vitamin Supplements and Gabapentin, Tiagabine, Pregabalin, etc. drugs.

In an embodiment of the invention, a first layer containing Gabapentin formulated for controlled release, wherein the controlled release profile is configured to maintain therapeutic levels of Gabapentin in the plasma for a prolonged period of time, and a second layer containing Duloxetine hydrochloride (HCl) formulated with an enteric coating to enable delayed release, wherein the enteric coating prevents the release of Duloxetine HCl in gastric fluid and facilitates release in the small intestine.

In an embodiment of the invention, the tablet is configured for modulated release, such that: Gabapentin provides controlled release, and Duloxetine (HCl) is released in the intestine for long-term therapeutic effect.

Accordingly, the present invention provides a process for preparing the multi- drug delivery composition comprising:
a) forming the first tablet by forming granules or microbeads or nanobeads or micropellets or nanopellets or microgranules or nanogranules of the pharmaceutically active substance along with pharmaceutically acceptable excipients and compressing these granules to form the first tablet;
b) forming the second tablet by forming granules or microbeads or nanobeads or micropellets or nanopellets or microgranules or nanogranules or such like form(s) of the pharmaceutically active substance along with pharmaceutically acceptable excipients and compressing these granules to form the second tablet;
c) optionally coating the first and/or second tablet(s); and
d) incorporating the first and second tablets in a suitable carrier selected from a shell, capsule, container and cartridge.

DESCRIPTION OF THE INVENTION
In one aspect, a multi-drug delivery composition is provided wherein the composition includes a first tablet, and a second tablet and the first and second tablet are conjoined together.

In an embodiment, a multi-drug delivery composition is provided wherein the composition includes a first tablet, and a second tablet and the first tablet is incorporated into the second tablet or vice versa.

In another aspect, a multi-drug delivery composition is provided wherein the composition includes a first tablet, and a second tablet and the first and second tablet are incorporated together in a carrier casing.

In an embodiment, a multi-drug delivery composition is provided wherein the composition includes a first tablet, and a second tablet and the first and second tablet are incorporated together in a carrier such as shell, capsule, container or cartridge.

In an embodiment, one or both of the first and second tablet has a continuous phase and a discontinuous phase.

In another embodiment, the discontinuous phase could be microbeads or nanobeads or micropellets or nanopellets or granules or microgranules or nanogranules and the like form(s).

In another aspect, the present invention is directed towards a process for preparing the multi- drug delivery composition comprising:
h) forming the first tablet by forming granules of the pharmaceutically active substance along with pharmaceutically acceptable excipients and compressing these granules to form the first tablet;
i) forming the the discontinuous phase;

j) forming the granules of the pharmaceutically active substance of the continuous phase along with pharmaceutically acceptable excipients;
k) mixing the granules of continuous phase with the the discontinuous phase;

l) compressing the mixture of above step to form the second tablet;

m) compressing the first tablet and the second tablet together to form the single tablet;

n) coating the single tablet to get the multi-drug delivery composition .

In another aspect, the present invention is directed towards a process for preparing the multi- drug delivery composition comprising:
e) forming the first tablet by forming granules or microbeads or nanobeads or micropellets or nanopellets or microgranules or nanogranules of the pharmaceutically active substance along with pharmaceutically acceptable excipients and compressing these granules to form the first tablet;
f) forming the second tablet by forming granules or microbeads or nanobeads or micropellets or nanopellets or microgranules or nanogranules or such like form(s) of the pharmaceutically active substance along with pharmaceutically acceptable excipients and compressing these granules to form the second tablet;
g) optionally coating the first and/or second tablet(s)

h) incorporating the first and second tablets in a suitable carrier selected from a shell, capsule, container and cartridge.

In one aspect, a multi-drug delivery composition is provided wherein the composition includes a first tablet layer , and a second layer tablet and the first and second tablet are conjoined together.

In another aspect, a multi-drug delivery composition is provided wherein the composition includes a first tablet, and a second tablet and the first and second tablet are not conjoined together but are incorporated into a carrier.

In an embodiment, the composition of present invention may be configured such that the first tablet and the second tablet comprise at least one pharmaceutically active substance, and pharmaceutically acceptable excipients.

In another embodiment, the second tablet of the composition of present invention when comprising more than one pharmaceutically active substance, said active substances are different from each other.

In yet another embodiment of the present invention, the first tablet and the second tablet are configured for modulated release of pharmaceutically active substance.

In another embodiment of the present invention, the release kinetics of pharmaceutically active substances may be different in first tablet from the release kinetics of pharmaceutically active substances comprising the second tablet.

In another embodiment of the present invention, the pharmaceutically active substances comprising the second tablet may have different release kinetics from each other.

In yet another embodiment of the present invention, the pharmaceutically active substance comprising the first tablet exhibits an immediate or delayed or controlled release profile.

In another embodiment of the present invention, the pharmaceutically active substance comprising the second tablet exhibits an immediate or delayed or controlled release profile.

In another embodiment of the present invention, the pharmaceutically active substance comprising the first tablet upon dissolution exhibits at least from about 50 to about 60% (by weight) of dissolution of the active within a period of about 15 minutes, particularly from about 60 to about 70% (by weight) of dissolution of the active within a period of about 30 minutes, and more particularly from about 70 to about 90% (by weight) of dissolution of the active within a period of about 45 minutes as measured by in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at
37°C.

In an embodiment of the present invention, the pharmaceutically active substance comprising the second tablet upon dissolution exhibits at least from about 50 to about 60% (by weight) of dissolution of the active within a period of about 15 minutes, particularly from about 60 to about 70% (by weight) of dissolution of the active within a period of about 30 minutes, and more particularly from about 70 to about 90% (by weight) of dissolution of the active within a period of about 45 minutes as measured by in-vitro dissolution in a USP Apparatus 1 (basket) at 100 rpm in 900 ml simulated gastric fluid without enzymes (SGF) at 37°C.

In another embodiment of the present invention the pharmaceutically active substance comprising the second tablet upon dissolution exhibits at least from about 70%±10% or
70%±20% or 70%±30% or 70%±40% of the second and third drug in the second tablet dissolve after 30 minutes when using USP apparatus 2 at 50 rpm, pH 6.8, and
37.5±0.5°C.

In one embodiment of the present invention, the first tablet is coated on the second tablet.

In another embodiment of the present invention, the first and the second tablet are conjoined parallel to each other.

In yet another embodiment of the present invention, the first tablet has pharmaceutically active substance dispersed throughout the tablet.

In an embodiment of the present invention, the first tablet is a gastro-retentive tablet which exhibits either immediate or controlled release of the pharmaceutically active substance contained therein.

In yet another embodiment of the present invention, the gastro-retentive tablet is in the form of a floating tablet.

In another embodiment of the present invention the drug(s) will be released from gastro- retentive tablet over an extended period of time, about 3 to about 12 hours, preferably about 4 to about 9 hours, more preferably at least about 5 hours, to the upper gastrointestinal (GI) tract.

In another embodiment of the present invention, the second tablet has a continuous phase and a discontinuous phase.

In yet another embodiment of the present invention, the continuous phase of the second tablet comprises a pharmaceutically active substance and pharmaceutically acceptable excipients.

In another embodiment of the present invention, the discontinuous phase of the second tablet is in the form of microbeads or nanobeads or micropellets or nanopellets or granules or microgranules or nanogranules or like form either comprising a pharmaceutically active substance alone or with pharmaceutically acceptable excipients.

In yet another embodiment of the present invention, the discontinuous phase of the second tablet comprises a pharmaceutically active substance and pharmaceutically acceptable excipients wherein the pharmaceutically active substance in the discontinuous phase is different from the pharmaceutically active substance present in the continuous phase.

In an embodiment of the present invention, the discontinuous phase of the second tablet comprises of more than one pharmaceutically active substance.

In an embodiment of the present invention the discontinuous phase of the second tablet exhibits delayed or controlled release of the pharmaceutically active substance contained therein.

In an embodiment of the invention the delayed release component composition comprises at least one enteric polymer.

In another embodiment of the invention the delayed release component provided by the present invention is characterized in that the enteric polymer is selected from polyvinyl alcohol acetate phthalate, cellulose acetate phthalate, 1,2,4-benzenetricarboxylic acid acetic acid Cellulose, hydroxypropyl methylcellulose phthalate, 1,2,4-benzenetricarboxylic acid hydroxypropyl methylcellulose, cellulose acetate succinate, hypromellose acetate succinate, hydroxyl acetate Propyl methylcellulose phthalate, methacrylic acid-ethyl acrylate copolymer, methyl vinyl ether-maleic anhydride copolymer, methacrylic acid-ethyl acrylate copolymer aqueous dispersion, methacrylic acid-methacrylate Methyl acrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate copolymer, polyvinyl acetate, ethyl cellulose, polyvinyl acetate and polyvinyl pyrrolidone K30 mixture. It is preferably hypromellose acetate succinate, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methylcellulose phthalate.

In some embodiments, the methacrylic acid-ethyl acrylate copolymer is a 1:1 copolymer, corresponding to commercially available Eudragit l 100-55 or Kollicoat MAE100P.

In some embodiments, the methyl vinyl ether-maleic anhydride copolymer corresponds to the commercially available Gantrez® ES series.

In some embodiments, the methacrylic acid-methyl methacrylate copolymer is a 1:1 or 1:2 copolymer, corresponding to Eudragit L100 and Eudragit S100, respectively.

In some embodiments, the enteric polymer of the present invention is a Eudragit polymer, such as Eudragit L, Eudragit S or Eudragit L 100-55.

In another embodiment of the present invention, the delayed release drug component containing the enteric polymer according to the present invention releases the drug under the condition of pH = 5.

In an embodiment of the present invention the suitable polymers for use in the composition of present invention may be linear, branched, dendrimeric, or star polymers, and include synthetic hydrophilic polymers as well as semi-synthetic and naturally occurring hydrophilic polymers. The polymers may be homopolymers or copolymers, if copolymers, either random copolymers, block copolymers or graft copolymers. Synthetic hydrophilic polymers useful herein include, but are not limited to: polyalkylene oxides, particularly poly(ethylene oxide), polyethylene glycol and poly(ethylene oxide)-poly(propylene oxide) copolymers; cellulosic polymers; acrylic acid and methacrylic acid polymers, copolymers and esters thereof, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl metbacrylate, ethyl methacrylate, and copolymers thereof, with each other or with additional acrylate species such as aminoethyl acrylate;maleic anhydride copolymers; polymaleic acid; poly(acrylamides) such as polyacrylamide per se, poly(methacrylamide), poly(dimethylacrylamide), and poly(N-isopropyl-acrylamide); poly(olefinic alcohol)s such as poly(vinyl alcohol), poly(N-vinyl lactams) such as poly(vinyl pyrrolidone), poly(N-vinyl caprolactam), and copolymers thereof polyols such as glycerol, polyglycerol (particularly highly branched polyglycerol), propylene glycol and trimethylene glycol substituted with one or more polyalkylene oxides, e.g., mono-, di- and tri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, and mono- and di-polyoxyethylated trimethylene glycol; polyoxyethylated sorbitol and polyoxyethylated glucose; polyoxazolines, includingpoly(methyloxazoline) and poly(ethyloxazoline); polyvinylamines; polyvinylacetates, including polyvinylacetate per se as well as ethylene-vinyl acetate copolymers, polyvinyl acetate phthalate, and the like, polyimines, such as polyethyleneimine; starch and starch- based polymers; polyurethane hydrogels; chitosan; polysaccharide gums; zein; and shellac, ammoniated shellac, shellac-acetyl alcohol, and shellac n-butyl stearate.

In another embodiment of the present invention the suitable polymers for use in the composition of present invention are cellulose polymers and their derivatives (such as for example, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, and microcrystalline cellulose, polysaccharides and their derivatives, polyalkylene oxides, polyethylene glycols, chitosan, poly(vinyl alcohol), xanthan gum, maleic anhydride copolymers, poly(vinyl pyrrolidone), starch and starch-based polymers, poly(2-ethyl-2- oxazoline), poly(ethyleneimine), polyurethane hydrogels, and crosslinked polyacrylic acids and their derivatives. Further examples are copolymers of the polymers listed in the preceding sentence, including block copolymers and grafted polymers.The terms “cellulose” and “cellulosic” are used herein to denote a linear polymer of anhydrogiucose. Preferred cellulosic polymers are alkyl-substituted cellulosic polymers that ultimately dissolve in the gastrointestinal (GI) tract in a predictably delayed manner. Preferred alkyl-substituted cellulose derivatives are those substituted with alkyl groups of 1 to 3 carbon atoms each. Examples are methylcellulose, hydroxymethyl-cellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose. In terms of their viscosities, one class of preferred alkyl-substituted celluloses includes those whose viscosity is within the range of about 100 to about 110,000 centipoise as a 2% aqueous solution at 200C. Another class includes those whose viscosity is within the range of about
1,000 to about 4,000 centipoise as a 1% aqueous solution at 20° C.

In an embodiment of the present invention the suitable polymers for use in the composition of present invention the amount of polymer relative to the drug can vary, depending on the drug release rate desired and on the polymer, its molecular weight, and excipients that may be present in the formulation. The amount of polymer will be sufficient however to retain at least about 50% of the drugs within the matrix one hour after ingestion (or immersion in the gastric fluid). Preferably, the amount of polymer is such that at least 55%, 60%, 65%, 70%, 75%, or 80% of the drugs remains in the extended-release matrix one hour after ingestion. The amount of polymer is such that at least 20%, 25%, 30%, 35%, 40% or 45% of the drugsremains in the extended-release matrix four hours after ingestion. The amount of polymer is such that at least 75%, 80%, or 85% of the drugs is released within six hours after ingestion. In all cases, however, the drugs will be substantially all released from the matrix within about ten hours, and preferably within about eight hours, after ingestion, and the polymeric matrix will remain substantially intact until all of the drug is released. The term “substantially intact” is used herein to denote a polymeric matrix in which the polymer portion substantially retains its size and shape without deterioration due to becoming solubilized in the gastric fluid or due to breakage into fragments or small particles.

In an embodiment of the present invention the water-swellable polymers can be used individually or in combination. Certain combinations will often provide a more controlled release of the drug than their components when used individually. Examples are cellulose- based polymers combined with gums, such as hydroxyethyl cellulose or hydroxypropyl cellulose combined with xanthan gum. Another example is poly(ethylene oxide) combined with xanthan gum.

In an embodiment of the invention the gastric retentive or floating nature and release profiles of a dosage form will depend partially upon the molecular weight of the swellable polymer. The polymers are preferably of a moderate to high molecular weight (900,000 Da to 4,000,000 Da) to enhance swelling and provide control of the release of the opioid and acetaminophen via erosion of the polymer matrix. An example of suitable polyethylene oxide polymers are those having molecular weights (viscosity average) on the order of 900,000 Da to 2,000,000 Da. Using a lower molecular weight (“MW”) polyethylene oxide, such as POLYOX™ 1105 (900,000 MW) release for both drugs are higher. Using a higher molecular weight polyethylene oxide (such as POLYOX™ N-60K (2,000,000 MW) or POLYOX™ WSR-301 (4,000,000 MW) reduces the rate of release for both drugs.

In one embodiment of the invention, a hydroxypropylmethylcellulose polymer of such molecular weight is utilized so that the viscosity of a 1% aqueous solution is about 4000 cps to greater than 100,000 cps.

In yet another embodiment of the present invention a typical dosage form should swell to approximately 115% of its original volume within 30 minutes after administration, and at a later time should swell to a volume that is 130% or more of the original volume.

In another embodiment of the present invention the dosage forms prepared for oral administration according to the present disclosure will generally contain other inactive additives (excipients) such as binders, lubricants, disintegrants, fillers, stabilizers, surfactants, coloring agents, and the like.

In another embodiment of the present invention binders are used to impart cohesive qualities to a tablet, and thus ensure that the tablet remains intact after compression. Suitable binder materials include, but are not limited to, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, waxes, and natural and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, microcrystalline cellulose, ethyl cellulose, hydroxyethyl cellulose, and the like), and Veegum.

In another embodiment the suitable inert fillers that can be used include lactose, mannitol, starch, sucrose, glucose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, ethylcellulose, hydroxypropyl methylcellulose phthalate, diacetylated monoglycerides, talc, titanium dioxide and other excipients. The amount of filler can range from about 10% to about 90% by weight of the tablet.

In another embodiment of the present invention, lubricants are used to facilitate tablet manufacture, promoting powder flow and preventing particle capping (i.e., particle breakage) when pressure is relieved. Useful lubricants are magnesium stearate (in a concentration of from 0.25 wt % to 3 wt %, preferably 0.2 wt % to 1.0 wt %, more preferably about 0.3 wt %), calcium stearate, stearic acid, and hydrogenated vegetable oil (preferably comprised of hydrogenated and refined triglycerides of stearic and palmitic acids at about 1 wt % to 5 wt %, most preferably less than about 2 wt %).

In another embodiment of the present invention, disintegrants are used to facilitate disintegration of the tablet, thereby increasing the erosion rate relative to the dissolution rate, and are generally starches, clays, celluloses, algins, gums, or crosslinked polymers (e.g., crosslinked polyvinyl pyrrolidone), sodium starch glycolate or sodium croscarmellose. The amount of disintegrant can range from about 0.5% to about 30% by weight of the tablet.
In another embodiment of the present invention, fillers include, for example, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose, and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, lactose monohydrate, dextrose, sodium chloride, and sorbitol.

In another embodiment of the present invention, solubility-enhancers including solubilizers per se, emulsifiers, and complexing agents (e.g., cyclodextrins), may also be advantageously included in the present formulations.

In another embodiment of the present invention, stabilizers, as well known in the art, are used to inhibit or retard drug decomposition reactions that include, by way of example, oxidative reactions.

In another embodiment of the present invention, the formulations are typically in the form of tablets.

In another embodiment of the present invention, the first tablet, the continuous phase of second tablet, and the discontinuous phase of the second tablet are prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts, e.g., in Gennaro, A. R., editor. “Remington: The Science & Practice of Pharmacy”, 21st ed., Williams & Williams, and in the “Physician's Desk Reference”, 2006, Thomson Healthcare.

In an embodiment of the present invention, the final single tablet composition is a stable product that does not fracture into first tablet and second tablet during storage and transport. This is measured, in part, in terms of friability and hardness.

In an embodiment of the invention the first tablet is produced by methods commonly known in the field of the invention. Such methods include dry granulation or wet granulation or direct compression which can be chosen by a person skilled in the art based on the characteristics of the pharmaceutically active substance or substances present in the first tablet.

In an embodiment of the present invention, the microbeads or nanobeads or micropellets or nanopellets or granules or microgranules or nanogranules or like form present in the second tablet and comprising the pharmaceutically active substance are formed by conventional
techniques known in the art to prepare enteric coated microbeads or nanobeads or micropellets or nanopellets or granules or microgranules or nanogranules or like form.

In an embodiment of the present invention, the discontinuous phase comprising a pharmaceutically active ingredient is mixed with the dry mixture of comprising another pharmaceutically active substance to form a final resultant mixture. The final resultant mixture is either compressed directly or is granulated using conventionally known granulation techniques to form the second tablet.

In an embodiment of the present invention the first tablet and the second tablet prepared by the manner as described in above paragraphs are compressed together into a final single tablet composition.

In an embodiment of the present invention the first tablet and the second tablet prepared by the manner as described in above paragraphs are compressed separately and incorporated together into a carrier such as a shell, a capsule, a container or a cartridge to form the final composition composition.

In another embodiment of the present invention the compositions are assessed for their physicochemical characteristics such as Loss on Drying (LOD), bulk and tap densities, particle size distribution, hardness, friability, content uniformity, disintegration, and dissolution. The compositions of the present invention should meet the acceptable standards for said physico-chemical characteristics.

In an embodiment of the present invention finishing layers to be applied to the present product are of essentially the same types commonly used in pharmaceutical science to smooth, seal and colour enteric products, and may be formulated and applied in the usual manners.

In one embodiment, the present invention is directed toward a tablet pharmaceutical composition comprising:
a) a first tablet comprising a pharmaceutically active substance;

b) a second tablet comprising:

- a continuous phase comprising a pharmaceutically active substance;

- a discontinuous phase comprising at least a pharmaceutically active substance; and c) optionally, a polymer over-coating on the single tablet,
wherein the first tablet and second tablet are conjoined together, the first tablet exhibits immediate release, the continuous phase of second tablet exhibits immediate release and the discontinuous phase of the second tablet exhibits delayed release.
In another embodiment, the present invention is directed toward a tablet pharmaceutical composition comprising:
a) a first tablet comprising a pharmaceutically active substance;

b) a second tablet comprising:

- a continuous phase comprising a pharmaceutically active substance;

- a discontinuous phase comprising at least a pharmaceutically active substance; and c) optionally, a polymer over-coating on the tablet,
Wherein the first tablet and the second tablet are conjoined together and the first tablet exhibits controlled release, the continuous phase of the second tablet exhibits immediate release and the discontinuous phase of the second tablet exhibits controlled release.
In yet another embodiment, the present invention is directed toward a tablet pharmaceutical composition comprising:
a) a first tablet comprising a pharmaceutically active substance;

b) a second tablet comprising:

- a continuous phase comprising a pharmaceutically active substance;

- a discontinuous phase comprising at least a pharmaceutically active substance; and c) optionally, a polymer over-coating on the single tablet,
wherein the first tablet and second tablet are conjoined together , the first tablet exhibits controlled release, the continuous phase of the second tablet exhibits controlled release and the discontinuous phase of the second tablet exhibits delayed release.

In yet another embodiment, the present invention is directed toward a tablet pharmaceutical composition comprising:
a) a first tablet comprising a pharmaceutically active substance;

b) a second tablet comprising:

- a continuous phase comprising a pharmaceutically active substance;

- a discontinuous phase comprising at least a pharmaceutically active substance; and c) optionally, a polymer over-coating on the single tablet,
wherein the first tablet and second tablet are conjoined together, the first tablet is gastro- retentive and exhibits controlled release, the continuous phase of the second tablet exhibits immediate release and the discontinuous phase of the second tablet exhibits delayed release.
In yet another embodiment, the present invention is directed toward a tablet pharmaceutical composition comprising:
a) a first tablet comprising a pharmaceutically active substance;

b) a second tablet comprising:

- a continuous phase comprising a pharmaceutically active substance;

- a discontinuous phase comprising at least a pharmaceutically active substance; and c) optionally, a polymer over-coating on the single tablet,
wherein the first tablet and second tablet are conjoined together , the first tablet is gastro- retentive and exhibits controlled release, the continuous phase of second tablet exhibits immediate release and the discontinuous phase of the second tablet exhibits delayed release as well as immediate release.

In yet another embodiment, the present invention is directed toward a tablet pharmaceutical composition comprising:
a) a first tablet comprising a pharmaceutically active substance;

b) a second tablet comprising:

- a continuous phase comprising a pharmaceutically active substance;

- a discontinuous phase comprising at least a pharmaceutically active substance; and c) optionally, a polymer over-coating on the single tablet,
wherein the first tablet and second tablet are conjoined together, the first tablet is floating formulation and exhibits prolonged release, the continuous phase of second tablet exhibits immediate release and the discontinuous phase of second tablet exhibits delayed release as well as immediate release.

In yet another embodiment, the present invention is directed toward a pharmaceutical composition comprising:
a) a first tablet comprising a pharmaceutically active substance;

b) a second tablet comprising a second pharmaceutically active substance;

c) optionally, a polymer over-coating on the first or second tablet, or on both;

wherein the first tablet and second tablet are incorporated together in a carrier such as shell, capsule, container or cartridge and wherein the first tablet is a gastro-floating formulation and exhibits extended release, and the second tablet exhibits delayed release.
In one embodiment, the present invention is directed toward a pharmaceutical composition comprising:
a) a first tablet comprising a pharmaceutically active substance;

b) a second tablet comprising:
- a continuous phase comprising a pharmaceutically active substance;

- a discontinuous phase comprising at least a pharmaceutically active substance; and wherein the first tablet and second tablet are together in a carrier, the first tablet exhibits immediate release, the continuous phase of second tablet exhibits immediate release and the discontinuous phase of the second tablet exhibits delayed release.

In another embodiment, the present invention is directed toward a pharmaceutical composition comprising:
a) a first tablet comprising a pharmaceutically active substance;

b) a second tablet comprising:

- a continuous phase comprising a pharmaceutically active substance;

- a discontinuous phase comprising at least a pharmaceutically active substance; and wherein the first tablet and the second tablet are together in a carrier and the first tablet exhibits controlled release, the continuous phase of the second tablet exhibits immediate release and the discontinuous phase of the second tablet exhibits controlled release.

In yet another embodiment, the present invention is directed toward a pharmaceutical composition comprising:
a) a first tablet comprising a pharmaceutically active substance;

b) a second tablet comprising:

- a continuous phase comprising a pharmaceutically active substance;

- a discontinuous phase comprising at least a pharmaceutically active substance; and wherein the first tablet and second tablet are together in a carrier, the first tablet exhibits controlled release, the continuous phase of the second tablet exhibits controlled release and the discontinuous phase of the second tablet exhibits delayed release.

In yet another embodiment, the present invention is directed toward a pharmaceutical composition comprising:
a) a first tablet comprising a pharmaceutically active substance;

b) a second tablet comprising:

- a continuous phase comprising a pharmaceutically active substance;

- a discontinuous phase comprising at least a pharmaceutically active substance; and wherein the first tablet and second tablet are together in a carrier, the first tablet is gastro- retentive and exhibits controlled release, the continuous phase of the second tablet exhibits immediate release and the discontinuous phase of the second tablet exhibits delayed release.

In yet another embodiment, the present invention is directed toward a pharmaceutical composition comprising:
a) a first tablet comprising a pharmaceutically active substance;

b) a second tablet comprising:

- a continuous phase comprising a pharmaceutically active substance;

- a discontinuous phase comprising at least a pharmaceutically active substance;

wherein the first tablet and second tablet are together in a carrier, the first tablet is gastro- retentive and exhibits controlled release, the continuous phase of second tablet exhibits immediate release and the discontinuous phase of the second tablet exhibits delayed release as well as immediate release.

In yet another embodiment, the present invention is directed toward a pharmaceutical composition comprising:
a) a first tablet comprising a pharmaceutically active substance;

b) a second tablet comprising:

- a continuous phase comprising a pharmaceutically active substance;

- a discontinuous phase comprising at least a pharmaceutically active substance; and wherein the first tablet and second tablet are together in a carrier, the first tablet is gastro- floating formulation and exhibits prolonged release, the continuous phase of second tablet exhibits immediate release and the discontinuous phase of second tablet exhibits delayed release as well as immediate release.

In yet another embodiment of the present invention, the second tablet forms the core and the first tablet is coated onto this core to result in final tablet and the final tablet is coated by polymer coating.

In yet another embodiment of the present invention, the first tablet forms the core and the second tablet is coated onto this core to result in final single tablet and the single final tablet is coated by polymer coating.

In yet another embodiment of the present invention, at least one active substance is incorporated in a coating composition to be coated onto the first or the second tablet or the composition.

In yet another embodiment of the present invention, in the embodiments described hereinabove the discontinuous phase is coated with enteric polymers.

In another embodiment of the present invention, first part of the microbeads or nanobeads or micropellets or nanopellets or granules or microgranules or nanogranules or like form present in the second tablet comprise a pharmaceutically active substance and the remaining part of microbeads or nanobeads or micropellets or nanopellets or granules or microgranules or nanogranules or like form present in the second tablet comprise a pharmaceutically active substance which is different from the active present in such first part.

In another embodiment of the present invention, first part of the microbeads or nanobeads or micropellets or nanopellets or granules or microgranules or nanogranules or like form present in the second tablet comprise a pharmaceutically active substance and the remaining part of microbeads or nanobeads or micropellets or nanopellets or granules or microgranules or nanogranules or like form present in the second tablet comprise a pharmaceutically active substance which is different from the active substance present in such first part and is also different from the active substance present in the first tablet.

In an embodiment the discontinuous phase of the second tablet has enteric coating. The terms “enteric coating”, “enteric outer coating”, “enteric layer” or “enteric outer layer” have the same meaning and can be used interchangeably.

In an embodiment of the invention, the enteric coating should be inert or substantially non- interacting with the single, tablet core containing the drug.

In another embodiment of the present invention, the enteric coating may contain ingredients such as polymers, release rate controlling agents, lubricants, anti-tacking agents, colorants, pigments or other additives to obtain a tablet of good appearance.

In yet another embodiment of the present invention the amount of enteric coating in the discontinuous phase of the second tablet can range from about 0.1 parts to about 3 parts by weight of enteric coating per one part by weight tablet core (about 0.1-3 parts by weight enteric coating:one part tablet core).

In another embodiment of the present invention, suitable polymers that can be used in the enteric coating can include film-forming polymers such as anionic co-polymers based on methacrylic acid esters, commercially available as Eudragit L 100 and Eurdragit S 100, trademarks of Rohm, GmbH & Co., K G, Darmstadt, Germany. This enteric coating is insoluble below pH 5 and is thus resistant to gastric fluid. By salt formation in the neutral or
weakly alkaline medium of the intestinal fluid, the enteric coating dissolves stepwise at pH values greater than 5.5-7.5. Another suitable polymer that can be used includes HPMCP or HPMCAS, commercially available from the Shin-Etsu Chemical Co. Ltd. A sole polymer can be employed such as HPMCAS or a mixture of polymers can be used, such as Eudragit and HPMCP. Thus, polymers can be cellulose acetate phthalate, HPMCAS, HPMCP, polyvinylacetate phthalate, carboxymethylethylcellulose, acrylic acid polymers and co- polymers and methacrylic acid polymers and co-polymers. The non-interacting property of such enteric coatings can be obtained or enhanced by of the tablet core. The amount of each polymer employed in the enteric neutralizing free acids in the enteric polymer with an inorganic or organic alkaline material, such as sodium hydroxide, magnesium hydroxide, meglumine and the like. The neutralized polymer results in enhanced stabilization coating can range from about 5% to about 99% by weight of the composition.

In another embodiment of the present invention, suitable release rate controlling agents that can be used in the enteric coating can include lactose, mannitol, starch, sucrose, glucose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, ethylcellulose, HPMCP, diacetylated monoglycerides, talc or titanium dioxide. The amounts of release agent employed in the enteric coating can range from about 0.5% to about 95% by weight of the composition.

In another embodiment of the present invention, suitable lubricants that can be used in the enteric coating can include dry or solid lubricants such as magnesium stearate, calcium stearate, silicon dioxide, or sodium stearate and waxes, such as carnauba wax. The lubricant can be employed in both the enteric coating layer and in the core tablet (or tablet core). The percentage of lubricant in either the enteric coating layer or the core tablet can range from about 0.5 to about 30% by weight of each tablet portion, also from about 5 to about 25 percent by weight, also from about 10 to about 15 percent by weight. Such percentage of lubricant can be used in tablets prepared using either a wet granulation method and/or dry blending/compression.

In another embodiment of the present invention, suitable defoaming agent such as simethicone can also be incorporated into the coating dispersion up to about 5 percent by weight of the enteric coating layer.

In another embodiment of the present invention, suitable surfactant such as sodium lauryl sulfate can be used as a wetting agent to help disperse the lubricant into the enteric coating suspension or dispersion. The surfactant can be up to about 5 percent of the enteric coating layer.

In an embodiment of the present invention the final single tablet comprising enteric coating are then covered with one or more finishing polymer over-coating or tablet film coat(s) or layer(s) to obtain tablets of good appearance, smoothness, color or functionality, such as modified release. The maximum thickness of the applied over-coating layer(s) is normally limited by processing conditions and the desired dissolution or release profile. For example, the tablet film(s) can be a thin coat as compared to the enteric coating. The polymer over- coating can be water soluble or water soluble/swellable in water or have a solubility that is pH dependent. Further, the over-coating can be rapidly disintegrating or even insoluble in water. The materials for the over-coating layer can be pharmaceutically acceptable excipients, such as the same polymers used in the enteric coating layer, sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, acrylic acid co-polymers, carboxymethylcellulose sodium, phthalate, HPMCAS, Eudragit (Rohm Pharma Co., West Germany, acrylate co-polymer, amionic in character), polyvinylacetaldiethylaminoacetate, water soluble salts of enteric coating polymers, and waxes, used alone or in mixtures. Additives, such as plasticizers, colorants, pigments, fillers, anti-tacking and anti-static agents, such as for instance magnesium stearate, titanium dioxide, talc and other additives may also be included into the over-coating layer(s).

In an embodiment, the amount of polymer coating in the tablet can range from about 0.01 parts to about 1 part by weight of polymer coating per one part by weight tablet core (about
0.01—about 1 part by weight enteric coating:one part tablet core).

In another embodiment of the invention, the polymer over-coating or tablet film coat can be applied by spraying, coating or layering procedures in suitable equipment, such as coating pan, coating granulator or in a fluidized bed apparatus. In such procedures, water or other solvents may be used to solubilize the materials used for the polymer over-coating or tablet film coat.

In an embodiment of the present invention the first tablet comprises a pharmaceutically active substance selected from the group of Gabapentin, Duloxetine, Folic acid, Methylcobalamin, Vitamin C, Vitamin B6, Vitamin B3, vitamin Supplements and selective serotonin and norepinephrine reuptake inhibitors (SSNRIS) categories drugs.

In an embodiment of the present invention the first tablet comprises a pharmaceutically active substance selected from the group of Gabapentin, anticonvulsant category of Tiagabine, Pragabalin, Levitracetam drugs that can be incorporated in the first tablet i.e. in the gastro-retentive/gastro floating layer.

In another embodiment of the present invention the continuous phase of the second tablet comprises a pharmaceutically active substance selected from the group of Gabapentin, Duloxetine, Folic acid, Methylcobalamin, Vitamin C, Vitamin B6, Vitamin B3, vitamin Supplements and Gabapentin, Tiagabine, Pregabalin, etc. drugs.

In another embodiment of the present invention the continuous phase of the second tablet comprises a pharmaceutically active substance selected from the group of Gabapentin, anticonvulsant category of Tiagabine, Pragabalin, Levitracetam drugs that can be incorporated in the dispersed phase of the second tablet.

In yet another embodiment of the present invention the discontinuous phase of the second tablet comprises a pharmaceutically active substance selected from the group of Duloxetine, Gabapentin, Folic acid, Methylcobalamin, Vitamin C, Vitamin D, Vitamin B6, Vitamin B3, vitamin Supplements use as drugs.

In yet another embodiment of the present invention the discontinuous phase of the second tablet comprises a pharmaceutically active substance selected from the group of Duloxetine, Venlafaxine, Sibutramine & other SNRI category drugs that can be incorporated in the microbeads of the second tablet.

Gabapentin is a medication commonly used to treat conditions such as nerve pain, seizures, and restless leg syndrome. It works by modifying how nerves send signals to the brain, which helps to reduce pain and prevent seizures. It is often prescribed for neuropathic pain (pain caused by nerve damage, such as from diabetes or shingles), as well as for partial seizures in epilepsy. In some cases, gabapentin is also used to treat fibromyalgia and anxiety disorders. Available in tablet, capsule, and oral solution forms, gabapentin is generally well-tolerated, though it can cause side effects like dizziness, drowsiness, and fatigue. It is important to take the medication as prescribed and consult with a healthcare provider before making any changes to its use

Duloxetine is a medication primarily used to treat depression, anxiety, and certain types of chronic pain, such as fibromyalgia, diabetic neuropathy, and osteoarthritis. It is classified as a serotonin-norepinephrine reuptake inhibitor (SNRI), meaning it works by increasing the levels of serotonin and norepinephrine, two neurotransmitters in the brain that help regulate mood and pain perception. Duloxetine is often prescribed for major depressive disorder, generalized anxiety disorder, and chronic pain conditions, helping to improve both mood and pain management. Common side effects may include nausea, dry mouth, fatigue, and dizziness. As with any medication, it’s important to follow the prescribed dosage and consult a healthcare provider, especially when considering changes to the medication or stopping it altogether, as sudden discontinuation can lead to withdrawal symptoms

Folic acid is a synthetic form of folate, a B-vitamin (B9) that is essential for various bodily functions, including the production of DNA and red blood cells. It is particularly important during periods of rapid cell growth, such as pregnancy, to help prevent birth defects in the baby's brain and spine, like spina bifida. Folic acid is commonly taken as a supplement by pregnant women or those planning to become pregnant, as it helps ensure proper fetal development. It can also be used to treat or prevent folate deficiency, which can lead to anemia. In addition to supplements, folate is found naturally in foods like leafy green vegetables, legumes, nuts, and fortified cereals. While generally safe, excessive intake of folic acid through supplements can sometimes mask symptoms of a vitamin B12 deficiency, so it's important to follow recommended dosages

Methylcobalamin is a form of vitamin B12 that is commonly used to treat vitamin B12 deficiency and related conditions, such as pernicious anemia and neuropathy. It plays a crucial role in the production of red blood cells, DNA synthesis, and the proper functioning of the nervous system. Methylcobalamin is considered more bioavailable than other forms of vitamin B12, meaning it is more easily absorbed and utilized by the body. It is often prescribed as a supplement to improve symptoms like fatigue, weakness, and numbness or tingling in the hands and feet, which can be caused by B12 deficiency. Methylcobalamin is typically available in oral, sublingual, or injectable forms. While it is generally safe, excessive use can lead to side effects, so it’s important to follow the prescribed dosage and consult a healthcare provider if any issues arise.

Vitamin B6 (pyridoxine) is essential for brain function, nerve health, and the production of red blood cells. It helps in the synthesis of neurotransmitters like serotonin and supports immune function. Rich sources of B6 include poultry, fish, potatoes, and bananas.

Vitamin B3, or niacin, is essential for converting food into energy and supporting the nervous system, skin, and digestive health. It plays a key role in the metabolism of carbohydrates, fats, and proteins. Niacin can be found in foods like meat, poultry, fish, and whole grains. A deficiency in vitamin B3 can lead to pellagra, causing symptoms like dermatitis, diarrhea, and dementia. While generally safe, high doses from supplements may cause side effects like skin flushing and liver issues

Serotonin and norepinephrine reuptake inhibitors (SNRIs) are a class of medications that work by blocking the reuptake of both serotonin and norepinephrine, two key neurotransmitters in the brain. By inhibiting the reabsorption of these chemicals, SNRIs increase their levels in the brain, which can help improve mood, reduce anxiety, and enhance energy levels. This dual action makes SNRIs effective in treating a variety of conditions, including major depressive disorder, generalized anxiety disorder, and certain types of chronic pain, such as fibromyalgia and neuropathic pain. Common examples of SNRIs include venlafaxine, duloxetine, and desvenlafaxine. While they can be highly effective, SNRIs may cause side effects like nausea, dizziness, and changes in blood pressure, so they should be used under the supervision of a healthcare provider.

Tiagabine is a medication primarily used to treat epilepsy, specifically for managing partial seizures in adults and children. It works by increasing the activity of gamma-aminobutyric acid (GABA), a neurotransmitter that inhibits nerve activity in the brain. By enhancing GABA's effects, tiagabine helps to reduce excessive neuronal firing, which is associated with seizure activity. While it is effective in controlling seizures, tiagabine can also be prescribed off-label for conditions such as anxiety disorders. Common side effects include dizziness, fatigue, and difficulty concentrating. As with any anticonvulsant, it is important to take tiagabine exactly as prescribed and consult a healthcare provider for proper monitoring and dosage adjustments.

Pregabalin is a medication primarily used to treat nerve pain, epilepsy, and generalized anxiety disorder. It works by binding to calcium channels in the brain and spinal cord, which helps to reduce the release of neurotransmitters that cause pain and seizures. Pregabalin is often prescribed for conditions such as diabetic neuropathy, fibromyalgia, and post-herpetic neuralgia, as well as to control partial seizures in epilepsy. It can also be used to manage anxiety disorders in some cases. While generally well-tolerated, common side effects of pregabalin include dizziness, drowsiness, weight gain, and swelling. It is important to take the medication as prescribed, as sudden discontinuation can lead to withdrawal symptoms.

In another aspect, the present invention is directed towards a process for preparing the pharmaceutical tablet composition comprising:
a) forming the first tablet by forming granules of the pharmaceutically active substance along with pharmaceutically acceptable excipients and compressing these granules to form the first tablet;
b) forming the microbeads or nanobeads or micropellets or nanopellets or granules or microgranules or nanogranules or like form of the discontinuous phase;
c) forming the granules of the pharmaceutically active substance of the continuous phase along with pharmaceutically acceptable excipients;
d) mixing the granules of continuous phase with the microbeads or nanobeads or micropellets or nanopellets or granules or microgranules or nanogranules of the discontinuous phase;
e) compressing the mixture of above step to form the second tablet;

f) compressing the first tablet and the second tablet together to form the tablet;

g) coating the tablet to get the tablet composition.

In another aspect, the present invention is directed towards a process for preparing the pharmaceutical composition comprising:
a) forming the first tablet by forming granules or microbeads or nanobeads or micropellets or nanopellets or microgranules or nanogranules of the pharmaceutically
active substance along with pharmaceutically acceptable excipients and compressing these granules to form the first tablet;
b) forming the second tablet by forming granules or microbeads or nanobeads or micropellets or nanopellets or microgranules or nanogranules of the pharmaceutically active substance along with pharmaceutically acceptable excipients and compressing these granules to form the second tablet;
c) optionally coating the first and/or second tablet(s)

d) incorporating the first and second tablets in a suitable carrier selected from a shell, capsule, container and cartridge to form the pharmaceutical composition.

In another embodiment of the present invention the pharmaceutical tablet composition is prepared by use of tablet press with the first component granules in the first hopper and the second tablet mixture in the second hopper. The tablet press was set to obtain the target weight for the first tablet. The second hopper was opened and the tablet press was adjusted to obtain the target tablet weight of first and second component tablets together. Once the target weight was obtained the press was adjusted to obtain the target hardness. Once the hardness was obtained, the manufactured tablets were periodically monitored regarding the weight of the first tablet, and the weight, hardness, gauge and friability of the single tablet. The pharmaceutical tablet composition was film coated with pharmaceutically acceptable coating polymers such as Hydroxyproply methyl cellulose (HPMC), Methyl hydroxyethyl cellulose, Ethyl cellulose, Povidone and cellulosic derivative polymer to obtain final single tablet.

The preparation method includes wet granulation, dry granulation, powder direct compression and the like.

In an embodiment the present invention has the advantage of providing an oral pharmaceutical composition containing a drug in the form of a tablet that can provide improved stability of the drug contained therein against degradation and/or discoloration by moisture and/or heating.

In another embodiment the present invention provides another advantage that it provides an oral pharmaceutical composition containing a drug that allows control of the release rate of said drug within wide margins.

In yet another embodiment the present invention provides further advantages of effectively reducing the pill burden, increasing the compliance of patients in taking medications, improving the safety of medications and reducing the side effects of the gastrointestinal tract.

Bilayer Tablets of Gabapentin & Duloxetine
Gabapentin has a biological half-life of 5-7 hours which gives the scope for the development of Controlled release tablets. Controlled release tablets will help to reduce the dose dependency and improve patient compliance.

Duloxetine HCl produces a toxic substance called alpha-naphthol when duloxetine HCl is in contact with gastric fluid. Thus, duloxetine HCl when given orally needed a protective enteric coating that disable the delivery of duloxetine HCl in gastric fluid while enabling the drug delivery only in small intestine.
Tablet composition:
Example 1 Example 2 Example 3
Ingredients mg/tab mg/tab mg/tab
Gabapentin 600 600 600
Hydroxy propyl cellulose 40 40 40
Hypromellose 110 115 120
Isopropyl alcohol q.s q.s q.s
Dichloromethane q.s q.s q.s
Hydroxy propyl cellulose K100 160 160 160
L-HPC 11 15 15 15
Magnesium stearate 10 10 10
Layer I weight (mg) 935 940 945
Duloxetine pellets 80 80 80
Microcrystalline cellulose (PH 112) 299.5 299.5 299.5
Hydroxy propyl cellulose 10 10 10
Iron oxide red 0.5 0.5 0.5
Croscarmellose sodium 15 15 15
Povidone 45 45 45
Isopropyl alcohol q.s q.s q.s
Croscarmellose sodium 40 40 40
Magnesium stearate 5 5 5
Layer II weight (mg) 495 495 495
Bilayer Tablet weight (mg) 1425 1435 1440
Coating Material
EP -S- 199 White 16 26 26
Ferric Oxide (Lake ) 2 2 2
Isopropyl alcohol q.s q.s q.s
Dichloromethane q.s q.s q.s
Coated Tablets Avg .Wt (mg) 1453 1463 1468

Percentage of drug release
Example 1 Example 2 Example 3
DULOXETINE HCL
Acid Media (NMT 10%) 0 1 (0-2) 1(1 - 1)
Buffer Media
(Q.NLT 70% In 60 Minute) 94(83 - 98) 100 (95-103) 84(78 - 91)
Gabapentin
Media –0.06M HCL
1HR. 26(24 - 28) 21(20-22) 20(19 - 20)
3HR 54(52 - 55) 44(43-46) 41(40 - 42)
4HR 64(62 - 66) 54(52-56) 49(49 - 50)
6HR 79(77 - 81) 68(66-71) 57(55 - 58)
8HR 92(90 - 93) 82(80-85) 74(73 - 76)
12HR 98(97 - 98) 96(94-100) 95(94 - 96)

Comparative drug release of Gabapentin with reference sample
Reference sample Example 1 Example 2 Example 3
Gabapentin
Media –0.06M HCL
1HR. 24(22-26) 26(24 - 28) 21(20-22) 20(19 - 20)
3HR 39(36-42) 54(52 - 55) 44(43-46) 41(40 - 42)
4HR 61(57-65) 64(62 - 66) 54(52-56) 49(49 - 50)
6HR 78(72-85) 79(77 - 81) 68(66-71) 57(55 - 58)
8HR 93(86-100) 92(90 - 93) 82(80-85) 74(73 - 76)
12HR 94(93-94) 98(97 - 98) 96(94-100) 95(94 - 96)

Below mentioned results of example 1-3 show delayed release profile of Duloxetine and control release profile of Gabapentin in a single dosage form. The first tablet (Gabapentin layer) and the second tablet (Duloxetine HCL layer) are configured for modulating the release of drugs such that a first tablet exhibits control release and second tablet exhibits gastro-retention with immediate release of a second drug; upon dissolution within a patient.
Control release profile of Gabapentin in bilayer tablets similar to reference product of Gabapentin Tablets.

Manufacturing process for Example 1 - 3:
a) forming the first tablet by forming granules of the pharmaceutically active substance, Gabapentin along with pharmaceutically acceptable excipients Hydroxypropyl Methyl Cellulose (HPMC K100MCR), Hydroxypropyl Methyl Cellulose (HPMC K4M), and Hydoxypropyl cellulose polymers as matrix builders. and compressing these granules to form the first tablet;
b) forming the Duloxetine HCL delayed release micropellets of the discontinuous phase;
c) forming the granules along with pharmaceutically acceptable excipients Microcrystalline Cellulose (MCC) and Hydoxypropyl cellulose polymers of the continuous phase;
d) mixing the granules of continuous phase with the micropellets or nanopellets or granules or microgranules or nanogranules of the discontinuous phase;
e) compressing the mixture of above step to form the second tablet;
f) compressing the first tablet and the second tablet together to form the single tablet;
g) Coating the single tablet to get the final single tablet.
However, combining multiple drugs within the same dosage form can bring many physicochemical and pharmacodynamics interactions. Here stability data mentioned below represent stable formulation of fixed-dose combinations (FDCs).

Example 1 Example 2 Example 3
CONDITION (400C/75% RH) Initial 3M 6M Initial 3M 6M Initial 3M 6M
Assay of Gabapentin 102 101 99 103.5 100.2 98 97.5 97.8 97.00
Assay of Duloxetine 108.8 106 102 105.2 105.4 102 101.8 102.8 100.6
Related substance for GABAPENTIN
Gabapentin impurity A BQL 0.152 0.156 BQL 0.064 0.069 BQL 0.102 0.17
(NMT- 0.4%)
Specified unidentified Imp. (NMT-0.2%) BQL 0 0.07 BQL 0 0.08 BQL 0 0.067
Total Imp. (NMT-1%) 0.112 0.552 0.592 0.112 0.651 0.79 0.182 0.604 0.68
Related substance for DULOXETINE HCL
Unspecified Imp. BQL 0.00% 0.05% BQL 0.15% 0.08% BQL 0.15% 0.07%
(NMT-0.2%)
Total Imp. (NMT-1%) BQL 0.14% 0.18% BQL 0.41% 0.27% BQL 0.40% 0.29%
,CLAIMS:WE CLAIM:

1. A multidrug pharmaceutical composition comprising:
a first active ingredient formulated to exhibit a controlled release profile, wherein the release of the first active ingredient occurs in a sustained and controlled manner over an extended period of time; and
a second active ingredient formulated to exhibit a delayed release profile, wherein the release of the second active ingredient delayed for a predetermined period following administration.

2. The multidrug pharmaceutical composition as claimed in claim 1,
wherein the first active ingredient being selected from the group of Gabapentin, Duloxetine, Folic acid, Methylcobalamin, Vitamin C, Vitamin B6, Vitamin B3, vitamin Supplements and selective serotonin and norepinephrine reuptake inhibitors (SSNRIS) categories drugs; and
wherein the second active ingredient being selected from the group of Gabapentin, Duloxetine, Folic acid, Methylcobalamin, Vitamin C, Vitamin B6, Vitamin B3, vitamin Supplements and Gabapentin, Tiagabine, Pregabalin, etc. drugs.

3. The multidrug pharmaceutical composition as claimed in claim 1, wherein the first active ingredient being formulated with excipients to achieve controlled release of the first active ingredient over a period up to 24 hours.

4. The multidrug pharmaceutical composition as claimed in claim 1, wherein the second active ingredient being formulated with excipients configured to delay the release of the second active ingredient until the composition reaches the small intestine.

5. The multidrug pharmaceutical composition as claimed in claim 1, wherein the controlled release of the first active ingredient being composed of one or more polymers selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and carboxymethyl Cellulose sodium, methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, pregelatinized starch, sodium alginate, gelatin, agar, tragacanth, xanthan gum, guar gum, arab Gum, carrageenan, carboxyvinyl polymer, polyethylene oxide, vinyl acetate povidone polymer matrix, polyvinyl alcohol, polyvinylpyrrolidone, pullulan, sodium polyacrylate, polyoxyethylene, Polyoxypropylene diol.

6. The multidrug pharmaceutical composition as claimed in claim 1, wherein the enteric coating of the second layer being composed of one or more pH-sensitive polymers selected from polyvinyl alcohol acetate phthalate, cellulose acetate phthalate, 1,2,4-benzenetricarboxylic acid acetic acid Cellulose, hydroxypropyl methylcellulose phthalate, 1,2,4-benzenetricarboxylic acid hydroxypropyl methylcellulose, cellulose acetate succinate, hypromellose acetate succinate, hydroxyl acetate Propyl methylcellulose phthalate, methacrylic acid-ethyl acrylate copolymer, methyl vinyl ether-maleic anhydride copolymer, methacrylic acid-ethyl acrylate copolymer aqueous dispersion, methacrylic acid-methacrylate Methyl acrylate copolymer, ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate copolymer, polyvinyl acetate, ethyl cellulose, polyvinyl acetate and polyvinyl pyrrolidone K30 mixture. It is preferably hypromellose acetate succinate, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methylcellulose phthalate.

7. The multidrug pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition being a tablet.

8. A bilayer tablet comprising:
a first layer comprises first active ingredient formulated for controlled release, wherein the release of the first active ingredient occurs in a sustained and controlled manner over an extended period of time; and
a second layer comprises second active ingredient formulated with an enteric coating to exhibit a delayed release profile, wherein the release of the second active ingredient delayed for a predetermined period following administration.

9. A bilayer tablet as claimed in claim 8,
wherein a first layer comprising first active ingredient being selected from the group of Gabapentin, Duloxetine, Folic acid, Methylcobalamin, Vitamin C, Vitamin B6, Vitamin B3, vitamin Supplements and selective serotonin and norepinephrine reuptake inhibitors (SSNRIS) categories drugs;
wherein the second layer comprising second active ingredient being selected from the group of Gabapentin, Duloxetine, Folic acid, Methylcobalamin, Vitamin C, Vitamin B6, Vitamin B3, vitamin Supplements and Gabapentin, Tiagabine, Pregabalin, etc. drugs.

10. A bilayer tablet as claimed in claim 8 comprising:
a first layer containing Gabapentin formulated for controlled release, wherein the controlled release profile is configured to maintain therapeutic levels of Gabapentin in the plasma for a prolonged period of time, and
a second layer containing Duloxetine hydrochloride (HCl) formulated with an enteric coating to enable delayed release, wherein the enteric coating prevents the release of Duloxetine HCl in gastric fluid and facilitates release in the small intestine.

11. The bilayer tablet as claimed in claim 8, wherein the tablet is configured for modulated release, such that: Gabapentin provides controlled release, and Duloxetine (HCl) is released in the intestine for long-term therapeutic effect.

12. A process for preparing the multi- drug delivery composition comprising:
e) forming the first tablet by forming granules or microbeads or nanobeads or micropellets or nanopellets or microgranules or nanogranules of the pharmaceutically active substance along with pharmaceutically acceptable excipients and compressing these granules to form the first tablet;
f) forming the second tablet by forming granules or microbeads or nanobeads or micropellets or nanopellets or microgranules or nanogranules or such like form(s) of the pharmaceutically active substance along with pharmaceutically acceptable excipients and compressing these granules to form the second tablet;
g) optionally coating the first and/or second tablet(s); and incorporating the first and second tablets in a suitable carrier selected from a shell, capsule, container and cartridge