DESC:Form 2
The Patent Act 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(see section 10 and rule 13)
1. TITLE OF THE INVENTION
SUBLINGUAL FORMULATION COMPRISING METOCLOPRAMIDE AND METHOD OF PREPARATION THEREOF.
2. APPLICANT(S)
Name Nationality Address
IMCD India Private Limited Indian 1101-1103, One BKC, B Wing, C-66, G Block, Bandra Kurla Complex, Bandra East Mumbai, Maharashtra - 400051, India.

3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION-
The present invention is related to a sublingual formulation comprising metoclopramide and pharmaceutically acceptable inert excipients. The invention further discloses the method of preparation of sublingual formulation.

BACKGROUND OF THE INVENTION
Metoclopramide is a medication used for stomach and esophageal problems. It is commonly used to treat and prevent nausea and vomiting, to help with emptying of the stomach in people with delayed stomach emptying, and to help with gastroesophageal reflux disease. It is also used to treat migraine headaches.

Metoclopramide is available commercially as CLOPRA® in USA in the form of oral tablet 5mg and 10mg strength. It is available in the form of oral solution equivalent to 5mgbase/5ml as REGLAN® in USA.

The oral mucosa offers a preferable route for both local and systemic delivery of drugs. This delivery route extends numerous advantages over the other delivery routes such as oral, due to its rich blood supply, rapid onset of action, avoidance of the first pass metabolism as well as enzymatic degradation, which results in enhanced bioavailability, increased patient compliance, and ease of self-medication.

Orally disintegrating tablet dissolves on top of the tongue. Orally disintegrating tablet is an alternative dosage form for patients who have difficulty in swallowing. Also, the tablets can be taken without water. Metoclopramide is available commercially as REGLAN ODT® in the form of orally disintegrating tablets.

Sublingual formulations exert similar characteristics to orally disintegrating formulations such as the short residence time in the mouth, rapid disintegration and dissolution, both being crucial for drug absorption following administration of sublingual tablets. For this reason, sublingual tablet formulations should be designed to dissolve rapidly in saliva release the drug effectively, without the aid of water. Furthermore, for systemic effect, sublingual route provides faster absorption when compared to buccal route. In both cases; the hepatic first-pass effect as well as gastric degradation is avoided; therefore, the efficacy is enhanced. Up to date, numerous drugs have been investigated for sublingual and buccal delivery; however, there are few products available in the market, which are mostly fast dissolving formulations.

Sublingual formulation has to be placed under the tongue. The drug is absorbed by diffusing into the blood through mucosa under the tongue. Sublingual formulation generally works faster and is not affected by stomach acid or by the first pass effect of drug metabolism.

The mucosal lining in the mouth is permeable and active pharmaceutical ingredients can pass across the mucosal barrier to enter venous blood vessels circulating under the mucosa lining. Saliva from salivary gland has a pH of 5.5 to 7.0. The mucus is negatively charged and forms a gelatinous film that permits mucoadhesion of disintegrated particles/substances to the mucosal lining. The relative permeability of the mucosa lining together with accessible blood supply permits rapid absorption of an active pharmaceutical ingredient into the blood by sublingual administration and thus a rapid onset of pharmacological action.

Sublingual formulation development depends upon a number of factors, such as pH, molecular weight, and aqueous solubility of the drug. Based on these properties, a suitably soluble drug may diffuse too slowly through the mucosa to be effective. Also, the development of a product with appropriate dosage form like tablet, strip, film, spray or drop is essential based on the physicochemical properties of the drug.

An ideal sublingual tablet needs to fulfil several requirements, such as rapid tablet dissolution, good wettability, palatability (low particle size, taste masking without feeling gritty), less moisture sensitivity, enough mechanical strength and no friability, mucoadhesive nature, minimum thickness, stability.

Metoclopramide is available as sublingual tablet in Argentina as RILAQUIN SL® and RELIVERAN®.

PCT application WO2019175100 discloses a compressed pharmaceutical dosage form comprising metoclopramide or a salt thereof present at a concentration between 2 and 60% w/w based on the total weight of the dosage form, silica mesoporous particles, wherein the silica mesoporous particles have a diameter between 1 and 100 µm, as measured by SEM and (i) have a surface area between 200 and 1000 m2/g and/or (ii) a pore volume between 0.2 and 3 cm3/g and/or (iii) an average pore size between 2 and 250 nm; and the silica mesoporous particles are present at a concentration between 5 and 70% w/w based on the total weight of the dosage form and, optionally one or more pharmaceutically acceptable excipients, wherein the one or more active pharmaceutical ingredients is in admixture with and/or loaded into said silica mesoporous particles, wherein a ratio of unloaded versus loaded ingredient is between 100:1 and 1:100, and wherein a porosity of the dosage form is more than 5% and less than 45% as measured by Hg intrusion and/or N2 sorption, and wherein a hardness of the dosage form is more than 5 N and less than 30 N using a Schleuniger type hardness tester.

US publication US20040192781 discloses a method for abating manifestations of gastroparesis in a patient comprising the steps of: administering metoclopramide, or a pharmaceutically acceptable salt thereof, to a patient prior to the patient performing a prescribed gastroparesis causing event, wherein said metoclopramide is in a pharmaceutically acceptable immediate release oral formulation; and, performing, by the patient, the prescribed gastroparesis causing event, wherein the administration of the immediate release oral formulation abates the rapid onset of gastroparesis in the patient.

Nausea and vomiting can be caused by various conditions like Gastrointestinal (GI) conditions like peptic ulcers, gastritis and gastroparesis; seasickness and other motion sicknesses; early pregnancy; intense pain; food poisoning; indigestion; infections; migraine headaches; vertigo and certain smells or odors.

The challenge with the currently available dosage forms for Metoclopramide like oral tablets or orally disintegrating tablets is that a patient suffering from nausea and vomiting can throw up the tablet. Thus, there is a strong need for sublingual formulation that can be put under the tongue and quickly gets solubilized avoiding the drawback of currently available dosage forms.

The applicants have provided better taste masked sublingual formulation comprising metoclopramide which has optimum formulation characteristics.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide sublingual formulation comprising metoclopramide and pharmaceutically acceptable inert excipients.

Another objective of the present invention is to provide a sublingual formulation in the form of tablet.

Another objective of the present invention is to provide sublingual formulation comprising metoclopramide with optimum formulation characteristics like rapid tablet dissolution, good wettability, palatability (low particle size, taste masking without feeling gritty), less moisture sensitivity, enough mechanical strength and no friability, mucoadhesive nature, minimum thickness, stability.

Another objective of the present invention is to provide a process for preparation of sublingual formulation comprising metoclopramide.

SUMMARY OF THE INVENTION
Main embodiment of the present invention provides a taste masked sublingual formulation comprising metoclopramide and pharmaceutically acceptable inert excipients.

In an embodiment of the present invention provides a sublingual formulation comprising;
a) Metoclopramide;
b) Ion exchange resin as a taste-masking agent; and
c) Pharmaceutically acceptable inert excipients.

In an aspect of the embodiment, Metoclopramide and Ion exchange resin is present in the weight ratio of 1:2.

In an aspect of the embodiment, the pharmaceutically acceptable inert excipients are taste masking agent, disintegrant, adsorbent, diluent, glidant, lubricant, sweetener, solubilizer, mucoadhesive polymer, buffers and pH modulators and flavouring agent.

In an aspect of the embodiment, metoclopramide is present in concentration range of 2-20 % w/w.

In an aspect of the embodiment, the taste masking agent is present in concentration range of 1-25 % w/w.

In an aspect of the embodiment, the disintegrants is present in concentration range of 3-20 % w/w.

In an aspect of the embodiment, the adsordent is present in concentration range of 10-30 % w/w.

In an aspect of the embodiment, the diluent is present in concentration range of 15-30 % w/w.

In an aspect of the embodiment, the glidant is present in concentration range of 0.1-2 % w/w.

In an aspect of the embodiment, the lubricant is present in concentration range of 0.1-3 % w/w.

In an aspect of the embodiment, the sweetener is present in concentration range of 0.5-15 % w/w.

In an aspect of the embodiment, the flavouring agent is present in concentration range of 0.1-8 % w/w.

In an aspect of the embodiment, the sublingual oral formulation is tablet.

In another embodiment, the present invention relates to a sublingual formulation comprising
a) 2-20 % w/w of Metoclopramide;
b) 1-25 % w/w of Taste masking agent;
c) 3-20 % w/w of Disintegrant;
d) 5-30 % w/w of Adsorbent;
e) 25-55 % w/w Diluent;
f) 0.1-2 % w/w Glidant;
g) 0.1-3 % w/w Lubricant;
h) 0.5-15 % w/w Sweetener; and
i) 0.1-10 % w/w Flavouring agent.

In another embodiment, the present invention relates to Sublingual formulation comprising;
a) 9.85 % w/w of Metoclopramide;
b) 19.7 % w/w of Sodium polystyrene sulphonate as an Ion exchange resin;
c) 3.78 % w/w of Croscarmellose sodium as a Disintegrant;
d) 33.78 % w/w of Mannitol as a Diluent;
e) 0.83 % w/w of Fumed silica as a Glidant;
f) 6.6 % w/w of Sucralose and 2.5 % w/w of Acesulfame potassium as a Sweetener;
g) 15.39 % w/w of Copovidone as a Binder;
h) 1.66 % w/w of Magnesium stearate as a Lubricant;
i) 6.66 % w/w of Flavouring agent; and
j) Distilled water;
wherein the percentages are with respect to total weight of the formulation.

In another embodiment, the present invention relates to process for preparation of a sublingual formulation comprising metoclopramide.

In another embodiment, the present invention relates to process for preparation of sublingual formulation comprises steps of;
a) Mixing Metoclopramide and suitable quantity of ion exchange resin in water under stirring to form a Metoclopramide-resin complex;
b) Adding suitable quantities of disintegrant, diluent, glidant, sweetener, binder, colouring agent and flavouring agent to Metoclopramide-resin complex to form a mixture;
c) Lubricating the above mixture with magnesium stearate to form a blend;
d) Compressing the blend to obtain sublingual formulation in the form of tablets.

In another aspect of embodiment, the sublingual formulation is prepared using direct compression method.

BRIEF DESCRIPTION OF THE DRAWINGS:
The accompanying drawings are included to provide a further understanding of the present invention and are incorporated in and constitute a part of this specification. The drawings illustrate exemplary embodiments of the present invention and, together with the description, serve to explain the principles of the present disclosure.

Figure 1 illustrates % cumulative release of formulation batch F3

DESCRIPTION OF THE INVENTION
The present invention is related to a sublingual formulation comprising metoclopramide and pharmaceutically acceptable inert excipients.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.

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

The term "a" and "an" refers to one or to more than one (i.e., to at least one) of the grammatical object of the article. The information provided in this document, and particularly the specific details of the described exemplary aspects, is provided primarily for clearness of understanding and no unnecessary limitations are to be understood from there.

As used herein, the term "about" means that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, "about" means the numerical value can vary by ±10% and remain within the scope of the disclosed embodiments.

As used herein, the terms "treat," or "treatment" mean both therapeutic treatment or prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or obtain beneficial or desired clinical results. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of extent of condition, disorder or disease; stabilized (i.e., not worsening) state of condition, disorder or disease; delay in onset or slowing of condition, disorder or disease progression; amelioration of the condition, disorder or disease state or remission (whether partial or total), whether detectable or undetectable; an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient; or enhancement or improvement of condition, disorder or disease.

The term "pharmaceutically acceptable inert excipients", denotes any of the components of a pharmaceutical formulation other than the active and which are approved by regulatory authorities or are generally ‘regarded as safe’ for human or animal use. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient can perform more than one function.

An ‘Oral formulation’ refers to a pharmaceutical preparation designed to be administered through the mouth. It is one of the most common routes of drug delivery due to its ease of use, patient acceptance, and versatility.

A ‘Sublingual route of administration’ refers to sublingual route of administration involves placing a medication under the tongue, where it dissolves and is absorbed directly into the bloodstream through the sublingual mucosa, the lining of the mouth beneath the tongue.

A ‘Tablet’ refers to a pharmaceutical oral dosage form (oral solid dosage, or OSD) or solid unit dosage form. Tablets may be defined as the solid unit dosage form of medication with suitable excipients. It comprises a mixture of active substances and excipients, usually in powder form, that are pressed or compacted into a solid dose.

Sublingual tablets offer several advantages over other oral dosage forms, making them a preferred choice for certain medications and patient populations. The key benefits of sublingual tablets:

The sublingual mucosa, the lining of the mouth beneath the tongue, is highly vascularized, allowing for rapid absorption of medication into the bloodstream. This bypasses the first-pass effect in the liver, where some medications can be metabolized and rendered less effective. Sublingual tablets often lead to a faster onset of action compared to oral administration, particularly for medications that require a quick response.

The liver is the primary site of drug metabolism, where enzymes can break down medications before they reach the bloodstream. Sublingual administration allows medication to enter the bloodstream directly, bypassing the first-pass effect and ensuring that a higher proportion of the active drug reaches its target site. This is particularly beneficial for medications that are extensively metabolized by the liver.

Medications that are unstable in the stomach environment or poorly absorbed from the gut are often suitable for sublingual administration. This route can help preserve the integrity of the drug and facilitate efficient absorption.

Sublingual administration is generally convenient and non-invasive, requiring only the placement of the medication under the tongue. This makes it a suitable option for patients who have difficulty swallowing pills or have aversions to needles. Additionally, sublingual tablets are often portable and easy to carry, making them convenient for administration on the go.

For certain medications, sublingual administration can provide rapid relief of acute symptoms due to the fast absorption and onset of action.

Sublingual tablets can be formulated with taste-masking excipients to minimize unpleasant tastes or odours of the drug, enhancing palatability and patient acceptance. This is particularly important for medications with bitter or unpleasant tastes.

In some cases, sublingual administration can lead to reduced systemic exposure to the drug compared to oral administration. This is because a smaller amount of the drug may be absorbed into the bloodstream, potentially minimizing side effects and improving tolerability.

Sublingual tablets can be designed to provide varying doses of the medication, allowing for individualized treatment plans based on patient needs. This flexibility is particularly useful for medications that require titration.

In an embodiment of the present invention provides a sublingual formulation comprising;
a) Metoclopramide;
b) Ion exchange resin as a taste-masking agent; and
c) Pharmaceutically acceptable inert excipients.

Metoclopramide is a medication used to treat nausea and vomiting, including nausea and vomiting of pregnancy (NVP). It is also used to treat gastroparesis, a condition in which the stomach muscles do not work properly, and gastroesophageal reflux disease (GERD). Metoclopramide is a dopamine receptor antagonist, which means that it blocks the action of dopamine in the brain. This helps to reduce the activity of the vomiting center in the brain, which is responsible for controlling nausea and vomiting. Metoclopramide as used herein includes its pharmaceutically acceptable salts including hydrochloride salt.

In an aspect of the embodiment, the Metoclopramide and Ion exchange resin is present in the weight ratio of 1:2.

In an aspect of the embodiment, metoclopramide is present in concentration range of 2-20 % w/w. In preferred aspect, the concentration of metoclopramide is 9.85 % w/w.

In an aspect of the embodiment, the pharmaceutically acceptable inert excipients are taste masking agent, binders, disintegrant, absorbent, diluent, glidant, lubricant, sweetener, solubilizer mucoadhesive polymer, buffers and pH modulators and flavoring agent.

In an aspect of the embodiment, the pharmaceutically acceptable inert excipients are taste-masking agent, disintegrant, diluent, glidant, lubricant, sweetener, binder and flavouring agent.

This formulation includes taste masking agent. Taste masking agents are substances that are used to disguise or block the unpleasant taste of certain medications or other substances. They are commonly used in pharmaceutical formulations to improve patient compliance and acceptability. Taste masking can be achieved through a variety of mechanisms, including: Reducing the bitterness threshold, Altering the taste perception, Reducing the surface area of the bitter substance. Examples of taste masking agent are cellulose based polymers like hydroxypropyl cellulose, hydroxypropyl methylcellulose, Sodium carboxymethyl cellulose, acrylate based polymers like poly methyl methacrylate, Lipids like stearic acid, glycerly dibehenate, hydrogenated vegetable oils, glyceryl monostearate, lecithin, cyclodextrins, polyvinyl alcohol and polyethylene glycol based polymers, high molecular weight polyethylene glycols, ion exchange resins, flavor maskers, sweeteners, silicas and calcium silicates

Sodium polystyrene sulphonate is used as an ion exchange resin in sublingual tablets to enhance drug delivery by improving taste masking and reducing bitterness. In the sublingual formulation, it binds unwanted ions, making the tablet more palatable while ensuring rapid dissolution and absorption under the tongue. Its effectiveness in optimizing sensory characteristics, as seen in evaluations, makes it a suitable choice for improving the overall patient experience in sublingual drug administration.

In an aspect of the embodiment, the taste masking agent is present in concentration range of 1-25 % w/w. In preferred aspect, the concentration is 19.7 % w/w.

Diluents increase bulk of the composition to facilitate compression of the tablet. As used herein, diluents include, but are not limited to, compounds such as lactose, starch, sorbitol, mannitol, dextrose, tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugar, such as Di-Pac® (Amstar), hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate stearate, sucrose-based diluents, confectioner's sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzed cereal solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; sodium chloride, and the like.

Mannitol is commonly used as a diluent in sublingual tablets due to its favorable properties. It provides a sweet taste, which improves patient compliance, and has a cooling effect upon dissolution, enhancing the mouthfeel. Mannitol also dissolves quickly, facilitating rapid disintegration and absorption of the active ingredient in sublingual formulations, making it ideal for fast-acting medications.

In an aspect of the embodiment, the diluent is present in concentration range of 25-55 % w/w. In preferred aspect, the concentration is 33.78 % w/w.

Binders, as used herein, refer to compounds which impart cohesive qualities to the tableted formulation and include, but are not limited to, compounds such as alginic acid and salts thereof; cellulose derivatives such as carboxymethyl cellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g., Klucel®), ethyl cellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; bentonites; gelatin; polyvinylpyrrolidone/vinyl acetate copolymer; crosspovidone; povidone; starch, pregelatinized starch; tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), and lactose; a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, polyvinylpyrrolidone and its derivatives (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone® XL-10), larch arabinogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, lipids like stearic acid, glyceryl dibehenate, glycerol and PEG based fatty acid esters and the like.

Copovidone is commonly used as a binder in sublingual tablets due to its excellent binding properties and water solubility. It helps enhance the mechanical strength of tablets while allowing for rapid disintegration, a key requirement for sublingual administration. Copovidone also improves the uniform distribution of active ingredients, ensuring effective absorption through the sublingual mucosa.

In an aspect of the embodiment, the binder is present in concentration range of 4-30 % w/w. In preferred aspect, the concentration is 15.39 % w/w.

Disintegrants are essential excipients in tablet formulation, as they facilitate the rapid breakdown of the tablet into smaller particles upon contact with water. This disintegration process allows for efficient drug release and absorption. They work by swelling or wicking water into the tablet, leading to rapid disintegration. It is particularly useful for chewable tablets and orally disintegrating tablets (ODTs).

As used herein, the disintegrant includes low-substituted hydroxypropyl celluloses, cross-linked celluloses, cross-linked sodium carboxymethyl celluloses, cross-linked carboxymethyl celluloses, cross-linked croscarmelloses, cross-linked starches, sodium starch glycolate, crospovidone, chitosan or combinations thereof.

Croscarmellose sodium is commonly used as a superdisintegrant in sublingual tablets. It facilitates the rapid disintegration of the tablet upon contact with saliva, enhancing the dissolution of the active pharmaceutical ingredient (API) and promoting faster onset of action. This property makes it ideal for sublingual formulations where quick absorption through the mucous membranes is desired.

In an aspect of the embodiment, the disintegrants is present in concentration range of 3-20 % w/w. In preferred aspect, the concentration is 3.78 % w/w.

Lubricants and glidants are compounds that prevent, reduce or inhibit adhesion or friction of materials. Exemplary lubricants or glidants include, but are not limited to, stearic acid, calcium hydroxide, talc, sodium stearyl fumerate, a hydrocarbon such as mineral oil, or hydrogenated vegetable oil such as hydrogenated soybean oil (Sterotex®), higher fatty acids and their alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol (e.g., PEG4000) or a methoxypolyethylene glycol such as Carbowax™, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as Aersil, Aeropearl, a starch such as corn starch, silicone oil, a surfactant, and the like.

In sublingual tablet formulations, fumed silica is commonly used as a glidant to improve the flow properties of the powder blend, ensuring uniformity during the tableting process. Magnesium stearate acts as a lubricant, reducing friction between the tablet material and the equipment during compression, thereby preventing sticking and ensuring smooth tablet formation. Both excipients contribute to the efficient manufacturing and quality of sublingual tablets.

In an aspect of the embodiment, the glidant is present in concentration range of 0.1-2 % w/w. In another aspect of the embodiment, the lubricant is present in concentration range of 0.1-3 % w/w.

Flavoring agents and/or sweeteners useful in the formulations described herein, include, but are not limited to, compounds such as acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium (Sunett®), talin, sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.

In an aspect of the embodiment, the sweetener is present in concentration range of 0.5-15 % w/w. In another aspect of the embodiment, the flavouring agent is present in concentration range of 0.1-10 % w/w.

Adsorbents are used in tablets to aid processing (liquid to solid conversion, better compaction and flow) , which are crucial processes for rapid drug release and absorption.

As used herein, the adsorbent includes Sodium Alginate, colloidal silicon dioxide like Aeroperl 300, Mannitol (Pearlitol), Lactose (SuperTab), Sorbitol, Starches, Microcrystalline Cellulose, Croscarmellose sodium, Polyoxyethylene sorbitan monolaurate, Maltodextrin, Silica gel, Dextrose, dicalcium phosphate, calcium silicates like Zeopharm 600, magnesium aluminium silicates and mesoporous silicas, silicified MCC and MCC derivativesetc.

In an aspect of the embodiment, the adsorbent is present in concentration range of 10-30 % w/w.

As used herein, the solubilizers include anionic surfactants, cationic surfactants and non-ionic surfactants.

Examples of anionic surfactants include (a) carboxylates: alkyl carboxylates-fatty acid salts; carboxylate fluoro surfactants, (b) sulfates: alkyl sulfates (e.g., sodium lauryl sulfate); alkyl ethersulfates (e.g., sodium laureth sulfate), (c) sulfonates: docusates (e.g., dioctyl sodium sulfosuccinate); alkyl benzene sulfonates, (d) phosphate esters: alkyl aryl ether phosphates; alkyl ether phosphates. Sodium lauryl sulphate BP (a mixture of sodium alkyl sulfates, mainly sodium dodecyl sulfate,)

Cationic surfactants include quaternary ammonium and pyridinium cationic surfactants.

The non-ionic surfactant can be classified as polyol esters, polyoxyethylene esters, poloxamers. polyol esters include glycol and glycerol esters and sorbitan derivatives. Fatty acid esters of sorbitan (generally referred to as Spans) and their ethoxylated derivatives (generally referred to as Tweens).

Mucoadhesive polymers as used herein include chitosan, carbopol, polyacrylic acids, hydroxyl propyl-methyl cellulose, hydroxyethyl cellulose and methyl cellulose, tragacanth, sodium alginate, guar gum, xanthan gum, carrageenan, starch, gelatin, cellulose derivatives, ethyl cellulose, dextran, polycarbofil, polyvinyl alcohol, poly vinyl pyrrolidone, lectins and the like.

Various buffers and pH modulators can also be used in the formulation according to the invention.

In an aspect of the embodiment, the sublingual formulation comprises a dosage form but not limited to tablets, pellets, lozenges, films, powders, gel injections, sprays etc. In a preferred aspect, the oral formulation is tablet.

Various techniques for preparing sublingual tablets include direct compression method, melt granulation, dry and wet granulation, dispersion granulation, tablet moulding and freeze drying.

The direct compression method is commonly used for commercial manufacture of sublingual tablets. It is a simple and cost-effective process, as it employs ingredients that can be mixed well and do not require further granulation steps prior to lubrication and compression. Sublingual tablets manufactured by the direct compression method exhibit good mechanical strength and acceptably fast disintegration. Various excipients like direct compressible and soluble ingredients, lubricant and a superdisintegrant (for example Crospovidone, Microcrystalline cellulose etc.), dry binder, sweeteners and flavors are used in this method.

Tablets manufactured by the compression molding process exhibit rapid disintegration and dissolution, which is usually within 5–10 seconds. These tablets pose special challenges during handling and shipping, because of the poor mechanical strength, and may require special packaging. Alternatively, the mechanical strength of the tablets may be enhanced by employing a suitable binder. However, the binder level should be optimized to avoid any deleterious effects on disintegration and dissolution of the tablets. The formulations for the compression molding process typically contain soluble excipients to impart quick and complete dissolution, and taste modifiers for patient compliance. Molded tablets have also been prepared directly from a molten matrix, in which the drug is dissolved or dispersed (heat molding), or by evaporating the solvent from a drug solution or suspension at room pressure. The compression molding process involves moistening of the formulation blend with a solvent (usually hydro-alcoholic), followed by molding into tablets under low pressure. The moist tablets are finally dried. The lower compression pressure employed for molding and drying of the moist tablet produces a highly porous tablet structure with enhanced dissolution. The choice, ratio, and amount of granulating solvents are critical to the physicochemical characteristics, performance, and stability of the tablets, and should be optimized.

Melt granulation is an appropriate alternative to other wet granulation techniques which are used for water sensitive materials. Generally, organic or aqueous solvents are not demanded for the melt granulation process, hence the environmental requirements of organic solvent capture and recycling are eliminated, while the absence of water excludes the wetting and drying phases, making the entire process less energy- and time-consuming. Melt granulation method could be efficiently applied in order to enhance the stability of moisture sensitive drug and further to improve the poor physical properties of the drug substance. The binders used for Melt granulation could be either hydrophilic or hydrophobic. The selection of a meltable binder with a hydrophilic/hydrophobic feature is critical factor for the dissolution behavior of the drugs.

In wet granulation, powders are bound together using adhesives rather than by compacting as in the dry granulation process. The adhesive (usually called a binder) is incorporated in the form of a solution or suspension in a suitable liquid. The liquid should be non-toxic and is preferably water, although various other solvents may be considered, such as propan-2-ol and ethanol. These may be used alone or combined with other solvents. The granulation liquid is added to the powder under the influence of an impeller (in a high shear granulator), screws (in a twin screw granulator), or air (in a fluidized bed granulator). Agitation of the particles along with the added liquid produces bonding between the primary powder particles to produce wet granules. The final step of the wet granulation process is the evaporation of the solution, which leaves the original powder particles bound together with the adhesive binder. The granules can be milled to the desired dimensions.

Dry granulation is the process of forming particles—i.e., granulates or granules from dry powder or powder blend without adding liquid to aid in the process. In dry granulation, granules of the desired quality (density, particle size distribution, porosity) are generated in a two-step process by compacting and a subsequent milling step. The addition of binders with subsequent drying process is not required here.

The process of freeze drying (lyophilization) has advantages over the other processes, as the tablets made by this process have high porosity, and when placed under the tongue disintegrate and dissolve instantly. It is a process of choice for products that are unstable or are heat sensitive. The process involves lowering the temperature of the product in an aqueous medium to below freezing, followed by applying a high-pressure vacuum. To extract the water in the form of a vapor, which is collected as ice on a condenser, a gradual temperature rise is applied during the drying process. The product temperature at the ice sublimation interface and the formulation collapse temperature are critical to obtain a freeze-dried cake of quality structure. This process retains the physical structure and preserves the material for storage or transport. The resulting tablets are usually light and have highly porous structures that allow rapid dissolution or disintegration. The freeze-drying process may result in a product with an amorphous structure, leading to an enhanced dissolution rate. However, tablets manufactured by freeze drying process have poor stability at a higher temperature and humidity.

Following sublingual administration, the patients are advised to abstain from swallowing the tablet and avoid eating, drinking, or chewing to facilitate drug absorption through the oral mucosa. Even swallowing saliva is to be avoided, to prevent ingestion through the gastrointestinal tract where drug absorption may be inefficient. Because these aspects pose some inconvenience to the patient, they should be taken into account at the product development stage to improve patient compliance.

In another embodiment, the present invention relates to Sublingual formulation comprising;
a) 9.85 % w/w of Metoclopramide;
b) 19.7 % w/w of Sodium polystyrene sulphonate as an Ion exchange resin;
c) 3.78 % w/w of Croscarmellose sodium as a Disintegrant;
d) 33.78 % w/w of Mannitol as a Diluent;
e) 0.83 % w/w of Fumed silica as a Glidant;
f) 6.6 % w/w of Sucralose and 2.5 % w/w of Acesulfame potassium as a Sweetener;
g) 15.39 % w/w of Copovidone as a Binder;
h) 1.66 % w/w of Magnesium stearate as a Lubricant;
i) 6.66 % w/w of Flavouring agent; and
j) Distilled water;
wherein the percentages are with respect to total weight of the formulation.

In another embodiment, the present invention relates to process for preparation of sublingual formulation comprises steps of;
a) Mixing Metoclopramide and suitable quantity of ion exchange resin in water under stirring to form a Metoclopramide-resin complex;
b) Adding suitable quantities of disintegrant, diluent, glidant, sweetener, binder, colouring agent and flavouring agent to Metoclopramide-resin complex to form a mixture;
c) Lubricating the above mixture with magnesium stearate to form a blend;
d) Compressing the blend to obtain sublingual formulation in the form of tablets.

In another aspect of embodiment, the sublingual formulation is prepared using direct compression method.

Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.

EXAMPLES
Example 1 – Sublingual formulation according to the invention.
SN Ingredients Quantity (%w/w)
1 Metoclopramide 2 – 20
2 Taste masking agent 1-25
3 Disintegrant 3-20
4 Adsorbent 5 – 30
5 Diluent 25 – 55 %
6 Glidant 0.1-2
7 Binder 4-30
8 Lubricant 0.1-3
9 Sweetener 0.5-15
10 Flavouring agent 0.1- 10%
Table no. 1 - Sublingual formulation

EXAMPLE 2 – Sublingual tablet formulation according to the invention
SN Ingredients Quantity (mg/tab)
F1 F2 F3
1 Metoclopramide HCL (API) 11.82 11.82 11.82
2 Methyl methacrylate and diethyl aminoethyl methacrylate copolymer 24 - -
3 Beta-cyclodextrin - 35.46 -
4 Sodium polystyrene sulphonate (Amberlite IRP 69) - - 23.64
5 Crospovidone 10 10 -
6 Croscarmellose Sodium - - 4.54
7 Mannitol 31.18 19.72 40.53
8 Fumed silica 1 1 1
9 Sucralose 12 12 8
10 Acesulfame potassium 3 3 3
11 Bitter-masking agent (Flavouring agent) 5 5 2
12 Orange flavor 8 8 5
13 Peppermint flavor 2 2 1
14 KollidonVA 64/ Copovidone - - 18.47
15 Magnesium stearate 2 2 2
Table 2 – Sublingual tablet formulation batches

The formulation batch (F3) with Sodium polystyrene sulphonate, as taste masking agent was selected as the optimized formulation due to its highest ratings in sweetness, flavor intensity, and mouthfeel. Its balanced sensory profile made it the most preferred by the panelists among the three batches.

Manufacturing process for Sublingual formulation –
1) The API-resin complex was prepared by mixing the API and resin in water.
2) The API-resin complex, along with all the ingredients except magnesium stearate, was mixed in a blender for 10 minutes at 15 rpm.
3) The blend was then lubricated using magnesium stearate in a blender for 3 minutes at 15 rpm.
4) The lubricated blend was compressed using 6 mm punches.
5) Finally, the tablets were characterized by assessing their weight variation, assay, hardness, disintegration, and dissolution.

Example 3 – Characterization of Sublingual tablet formulation according to example 2
The formulation batches F1, F2 and F3 were further evaluated for weight, thickness, diameter, hardness, disintegration time, dissolution study and sensory evaluation.

• Weight, Thickness, Diameter, Hardness and Disintegration time of Sublingual tablet
Parameters F1 F2 F3
Weight 110 -113 mg 110 -113 mg 121 -123 mg
Thickness 3.47 mm 3.46 -3.53mm 3.71 -3.9mm
Diameter 6.06 mm 6.08–6.11 mm 6.03–6.07 mm
Hardness 20 -25 N 20 -25 N 27 -30 N
Disintegration time 26 seconds 106 seconds 44 seconds
Table 3 – Characterization result for Sublingual tablet formulation batches

• Dissolution study of Formulation batch F3
The dissolution test was performed using a USP Type I apparatus (basket) with a rotation speed of 100 rpm. The dissolution medium consisted of 900 mL of phosphate buffer (pH 6.8). Table 4 and Figure 1 refers to % Cumulative release for Formulation batch F3.

Time (mins) %Cumulative release
5 53.13 ±1.92
10 76.87 ±5.16
15 87.99 ±4.60
30 96.36 ±1.02
45 97.04 ±1.65
60 99.25 ±2.53
Table 4 – % Cumulative release for Formulation batch F3

• Sensory evaluation
The sensory evaluation test was conducted using a 9-point hedonic scale, with an average of five panelists rating the formulation batches. The formulations were assessed based on attributes like sweetness, bitterness, flavor, grittiness, and mouthfeel. The ratings on the 9-point scale were as follows:
• 9 - Like Extremely
• 8- Like Very Much
• 7 - Like Moderately
• 6 - Like Slightly
• 5 - Neither Like nor Dislike
• 4 - Dislike Slightly
• 3 - Dislike Moderately
• 2 - Dislike Very Much
• 1 - Dislike Extremely

The formulation batch (F3) with Sodium polystyrene sulphonate, as taste masking agent was selected as the optimized formulation due to its highest ratings in sweetness, flavor intensity, and mouthfeel. Its balanced sensory profile made it the most preferred by the panelists among the three batches.

Sample Sweetness Intensity Bitterness intensity Flavor intensity Grittiness Mouthfeel
F1 5.4 6.1 6.2 6.5 6.9
F2 4.5 3.8 4.9 6.9 6.7
F3 8.4 8.2 8.5 7.4 8.2
Table 5 - Sensory evaluation for formulation batches

We claim
1. A Sublingual formulation comprising;
a) Metoclopramide;
b) Ion exchange resin as a taste-masking agent; and
c) Pharmaceutically acceptable inert excipients.

2. The formulation as claimed in claim 1, wherein the sublingual formulation is in the form of tablet.

3. The formulation as claimed in claim 1, wherein Metoclopramide and Ion exchange resin is present in the weight ratio of 1:2.

4. The formulation as claimed in claim 1, wherein the Ion exchange resin is Sodium polystyrene sulphonate in a concentration range of 1-30% w/w.

5. The formulation as claimed in claim 1, wherein the ion exchange resin binds with Metoclopramide to mask the bitter taste and facilitate sublingual administration.

6. The formulation as claimed in claim 1, wherein the pharmaceutically acceptable inert excipients are taste-masking agent, disintegrant, diluent, glidant, lubricant, sweetener, binder and flavouring agent.

7. A Sublingual formulation comprising;
a) Metoclopramide in a concentration range of 2-20 % w/w;
b) Ion exchange resin/taste-masking agent in a concentration range of 1-30 % w/w;
c) Disintegrant in a concentration range of 3-20 % w/w;
d) Diluent in a concentration range of 12-55 % w/w;
e) Glidant in a concentration range of 0.1-2 % w/w;
f) Sweetener in a concentration range of 0.5-15 % w/w;
g) Binder in a concentration range of 4-30 % w/w;
h) Lubricant in a concentration range of 0.1-2 % w/w;
i) Flavouring agent in a concentration range of 0.1-10 % w/w; and
j) Distilled water.

8. A Sublingual formulation comprising;
a) 9.85 % w/w of Metoclopramide;
b) 19.7 % w/w of Sodium polystyrene sulphonate as an Ion exchange resin;
c) 3.78 % w/w of Croscarmellose sodium as a Disintegrant;
d) 33.78 % w/w of Mannitol as a Diluent;
e) 0.83 % w/w of Fumed silica as a Glidant;
f) 6.6 % w/w of Sucralose and 2.5 % w/w of Acesulfame potassium as a Sweetener;
g) 15.39 % w/w of Copovidone as a Binder;
h) 1.66 % w/w of Magnesium stearate as a Lubricant;
i) 6.66 % w/w of Flavouring agent; and
j) Distilled water;
wherein the percentages are with respect to total weight of the formulation.

9. A process for preparation of sublingual formulation comprises steps of;
a) Mixing Metoclopramide and suitable quantity of ion exchange resin in water under stirring to form a Metoclopramide-resin complex;
b) Adding suitable quantities of disintegrant, diluent, glidant, sweetener, binder, colouring agent and flavouring agent to Metoclopramide-resin complex to form a mixture;
c) Lubricating the above mixture with magnesium stearate to form a blend;
d) Compressing the blend to obtain sublingual formulation in the form of tablets.

10. The process as claimed is claim 9, wherein the sublingual formulation is prepared using direct compression method.

Dated this 01st October 2024

Vijaykumar Shivpuje,
Agent for the applicant
IN/PA 1096,
Sri Kripa, Akshay Nagar,
Old Ausa Road, Latur,
413531, Maharashtra, India

SUBLINGUAL FORMULATION COMPRISING METOCLOPRAMIDE AND METHOF OF PREPARATION THEREOF

ABSTRACT

The present invention relates to a taste masked sublingual formulation comprising metoclopramide. The formulation is in the form of tablet and comprises various excipients including taste masking agent, disintegrant, absorbent, diluent, glidant, lubricant, sweetener, solubilizer, mucoadhesive polymer, buffers and pH modulators and flavouring agent. The invention also provides a method of preparation for the sublingual formulation comprising metoclopramide.

,CLAIMS:We claim
1. A Sublingual formulation comprising;
a) Metoclopramide;
b) Ion exchange resin as a taste-masking agent; and
c) Pharmaceutically acceptable inert excipients.

2. The formulation as claimed in claim 1, wherein the sublingual formulation is in the form of tablet.

3. The formulation as claimed in claim 1, wherein Metoclopramide and Ion exchange resin is present in the weight ratio of 1:2.

4. The formulation as claimed in claim 1, wherein the Ion exchange resin is Sodium polystyrene sulphonate in a concentration range of 1-30% w/w.

5. The formulation as claimed in claim 1, wherein the ion exchange resin binds with Metoclopramide to mask the bitter taste and facilitate sublingual administration.

6. The formulation as claimed in claim 1, wherein the pharmaceutically acceptable inert excipients are taste-masking agent, disintegrant, diluent, glidant, lubricant, sweetener, binder and flavouring agent.

7. A Sublingual formulation comprising;
a) Metoclopramide in a concentration range of 2-20 % w/w;
b) Ion exchange resin/taste-masking agent in a concentration range of 1-30 % w/w;
c) Disintegrant in a concentration range of 3-20 % w/w;
d) Diluent in a concentration range of 12-55 % w/w;
e) Glidant in a concentration range of 0.1-2 % w/w;
f) Sweetener in a concentration range of 0.5-15 % w/w;
g) Binder in a concentration range of 4-30 % w/w;
h) Lubricant in a concentration range of 0.1-2 % w/w;
i) Flavouring agent in a concentration range of 0.1-10 % w/w; and
j) Distilled water.

8. A Sublingual formulation comprising;
a) 9.85 % w/w of Metoclopramide;
b) 19.7 % w/w of Sodium polystyrene sulphonate as an Ion exchange resin;
c) 3.78 % w/w of Croscarmellose sodium as a Disintegrant;
d) 33.78 % w/w of Mannitol as a Diluent;
e) 0.83 % w/w of Fumed silica as a Glidant;
f) 6.6 % w/w of Sucralose and 2.5 % w/w of Acesulfame potassium as a Sweetener;
g) 15.39 % w/w of Copovidone as a Binder;
h) 1.66 % w/w of Magnesium stearate as a Lubricant;
i) 6.66 % w/w of Flavouring agent; and
j) Distilled water;
wherein the percentages are with respect to total weight of the formulation.

9. A process for preparation of sublingual formulation comprises steps of;
a) Mixing Metoclopramide and suitable quantity of ion exchange resin in water under stirring to form a Metoclopramide-resin complex;
b) Adding suitable quantities of disintegrant, diluent, glidant, sweetener, binder, colouring agent and flavouring agent to Metoclopramide-resin complex to form a mixture;
c) Lubricating the above mixture with magnesium stearate to form a blend;
d) Compressing the blend to obtain sublingual formulation in the form of tablets.

10. The process as claimed is claim 9, wherein the sublingual formulation is prepared using direct compression method.