The present invention relates to a sustained release oral pharmaceutical composition of dicycloverine or salts, and/or solvates and methods of making and using the compositions to treat functional conditions involving smooth muscle spasm like functional bowel/irritable bowel syndrome. The sustained release composition of present invention exhibits sustained release of the dicycloverine for longer period in addition to sufficient release in initial hours to provide therapeutic relief.
Background of the invention
Dicycloverine hydrochloride is chemically known as [bicyclohexyl]-1-carboxylic acid, 2(diethylamino) ethyl ester, hydrochloride, with a molecular formula of C19H35NO2»HC1 and the following structural formula:
/. ·'*...... A € C- 3H
.........................< .........
Dicycloverine hydrochloride occurs as a fine, white, crystalline, practically odorless powder with a bitter taste. It is soluble in water, freely soluble in alcohol and chloroform, and very slightly soluble in ether.
Dicycloverine is anticholinergic antispasmotic agent and chemically synthetic tertiary amine, which inhibits the muscarinic actions of acetylcholine on autonomic nerve endings, decreasing gastrointestinal secretions and intestinal motility. Dicycloverine exhibits broad activity against muscarinic acetylcholine receptors, but has been mainly used for gastrointestinal conditions including peptic ulcer disease and gastrointestinal conditions associated with pain and spasm. In USA, dicycloverine was first approved for the treatment of peptic ulcer disease in 1996, but now a days, more commonly used as an antispasmotic to treat irritable bowel syndrome (IBS).
Dicycloverine is available in capsules and tablets of 10 and 20 mg generically and under the brand name Bentyl®. Oral syrups and solutions for injection are also available in USA. The typical oral dose in adults is 10 to 20 mg three to four times daily. Common side effects are those of parasympathetic stimulation and include dryness of the mouth and eyes, decreased sweating, headache, visual blurring, constipation, urinary retention, anxiety, restlessness and delusions. In Europe, it is available in immediate release tablets and oral solution form.
All currently marketed formulation of dicycloverine is available in immediate release formulations and therefore exhibit very rapid dissolution profile that results in a rapid rise in blood plasma concentrations of the drug shortly after administration (Tmax of approximately
1.5-3 hours) and is eliminated quickly with a short half-life (tl/2) of 1.8 hours. Short Tmax and half life end up in rapid increase and rapid decline in concentration of dicycloverine after administration and to maintain therapeutic efficacy, multiple dosing is to be administered. Therefore, conventional marketed dicycloverine formulations are to be administered multiple times a day in order to maintain, tolerable, therapeutic serum levels over a 24 hour period.
WO2010096820 Al discloses a controlled release composition of anti-cholinergic drugs in multiparticulate form where in core comprises anti-cholinergic drugs including dicyclomine and core coated by at least one water-insoluble polymer, which is further coated by enteric polymer optionally in combination with a water-insoluble polymer. The composition contain immediate release bead and controlled release bead which is further mixed and blended with other excipient to form a final formulation. This involves many steps and involve complex process.
US3065143 describes a dosage form of medicinal agents including dicyclomine which provide substantially constant rate of release over a period of at least 4 hours. Tablet dosage form was prepared by direct compression of medicinal agent with hydrophilic gum. Three examples of dicyclomine with gum to drug ratio were disclosed with ratio of 2:1, 5.7:1 and 10:1 which provided % drug release of 100% in 7 hrs, 100?zo in 9 hrs and 90% in 12 hours respectively. To achieve sustained release of drugs for period over 12 hours, very high concentration of hydrophilic gum is required which poses practical problem in formulating the dosage form.
Joshi et al., discloses a sustained release matrix tablet of dicyclomine hydrochloride using natural polysaccharide from xanthan gum, guar gum and pectin alone or in combinations. (IJPSR, 2014; Vol. 5(4): 1331-1338)
Thus, there is a need in the society for a composition or formulation of dicycloverine, which helps to provide therapeutic effective amount of drug within 1-2 hrs after administration and maintain therapeutic effective amount of drug for longer period to provide therapeutic effects. More particularly there is a need for composition or formulation of dicycloverine which maintain clinically effective and therapeutic levels of the drug over a longer period of time. There is also a need for a formulation which will allow for once-a-day dosing and thereby improve patient compliance. Further, there is a need for an oral formulation that has reduced side effects.
The present invention meets some or all of these aims.
Summary of the invention
The present invention is all about a sustained release oral pharmaceutical composition of dicycloverine or salts, and/or solvates and methods of making and using the compositions.
The main embodiment of the present invention is to provide a sustained release oral pharmaceutical composition comprising;
a. a core comprising 80 % to 95 % w/w of dicycloverine or a salt thereof, one or more binder, one polymer present intra granular and one polymer present extra granular and one or more inactive excipients,
b. film coating over core comprising 5% to 20% w/w of dicycloverine or a salt thereof, water soluble film forming polymer and one or more inactive excipients.
Yet another embodiment of the present invention is to provide a sustained release oral pharmaceutical composition comprising;
a. a core comprising 80 % to 95 % w/w of dicycloverine or a salt thereof, one or more binder, one hydrophilic polymer present intra granular and one hydrophobic polymer present extra granular and one or more inactive excipients,
b. film coating over core comprising 5% to 20% w/w of dicycloverine or a salt thereof, water soluble film forming polymer and one or more inactive excipients.
Yet another embodiment of the present invention is to provide a sustained release oral pharmaceutical composition comprising;
a. a core comprising 80 % to 95 % w/w of dicycloverine or a salt thereof, one or more binder, one hydrophobic polymer present intra granular and one hydrophilic polymer present extra granular and one or more inactive excipients,
b. film coating over core comprising 5% to 20% w/w of dicycloverine or a salt thereof, water soluble film forming polymer and one or more inactive excipients.
Still one more embodiment of the present invention is to provide a sustained release oral pharmaceutical composition comprising;
a. a core comprising 80 % to 95 % w/w of dicycloverine or a salt thereof, one or more binder, one hydrophilic polymer present intra granular and one hydrophilic polymer present extra granular and one or more inactive excipients,
b. film coating over core comprising 5% to 20% w/w of dicycloverine or a salt thereof, water soluble film forming polymer and one or more inactive excipients.
In still another embodiment, the present invention is directed to a method of treating functional conditions involving smooth muscle spasm like functional bowel/irritable bowel syndrome.
Detailed description of the invention
The present invention relates to a sustained release composition of dicycloverine and salts thereof. More particularly, the sustained release composition of dicycloverine and salts thereof which exhibits sustained release of the dicycloverine for longer period in addition to sufficient release in initial hours to provide therapeutic relief.
The term “dicycloverine” as used herein is the main active ingredient which is also known as dicyclomine and both represent the same active ingredient.
The term salts thereof' as used herein includes any salt prepared by conventional methods known in the art. Examples of such salts are acid addition salts formed by inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and the like; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gentisic acid, fumaric acid, lactobionic acid, salicylic acid, and the like; amino acid such as glycine, alanine, valine, isoleucine, serine, cysteine, cystine, aspartate, glutamine, lysine, arginine, tyrosine and proline; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and the like; metal salts formed by alkali metals such as sodium, potassium, and the like; and a salt formed by an ammonium ion and the like.
As per one embodiment, the dicycloverine or salts thereof is present in the range from about 10 mg to 1000 mg, preferably in the range from about 20 to 80 mg, more preferably in the range from about 30 to 60 mg.
As used herein, the term composition, as in pharmaceutical composition, is intended to encompass a drug product dicycloverine or its pharmaceutically acceptable salts thereof, and other inactive excipients. Such pharmaceutical compositions are synonymous with formulation and dosage form. Pharmaceutical composition of the invention include, but is not limited to, granules, tablets (single layered tablets, multilayered tablets, bioadhesive tablets, caplets, matrix tablets, tablet within a tablet, mucoadhesive tablets, capsules (immediate or modified release) (hard and soft or liquid filled soft gelatin capsules), pills, troches, microcapsules, mini- tablets, tablets in capsules and microspheres. Preferably, the pharmaceutical composition refers to tablets and capsules. More preferably, the pharmaceutical composition refers to sustained release oral tablets, which may be uncoated or film coated. More preferably the composition is in the form of film coated sustained release tablets.
The term “sustained release” as used herein refers to a composition designed to release a drug at a predetermined rate in order to maintain a constant drug concentration for a specific period of time with minimum side effects.
Sustained release drug formulations may provide an immediate dose required for the normal therapeutic response and a portion for subsequent delivery. The initially released amount is not the whole dose but just a part of the available dose which is sufficient to begin eliciting a therapeutic effect. This is then followed by the gradual release of the drug in amounts sufficient to maintain the therapeutic response over a specific extended period of time throughout the intended dosing interval. In the case of the present invention this period of sustained release is intended to be at least 12 hours, and more preferably is at least 16 hours. In preferred embodiments, the therapeutic effect is maintained for at least 20 hours, and most preferably for at least 24 hours. The release of the drug from the formulation is non-linear over time.
In certain embodiments, not more than 30% of the drug is released within an hour of administration. In some embodiments, at least 20% of the drug is released after 1 hour.
In some embodiments, not more than 60% of the drug is released after 6 hours from administration.
In some embodiments, not more than 85% of the drug is released in 12 hours from administration. More preferably not more than 65% of the drug is released in 12 hours.
In some embodiments, not more than 30% of the drug is released within an hour of administration and not more than 60% of the drug is released after 6 hours from administration.
Sustained release drug formulations normally demonstrate a non-linear release of drug. In contrast, controlled release formulations normally deliver the drug at a predetermined rate over a specified period. The release from a controlled release formulation is usually linear with respect to time and controlled release formulations are intended to lead to fairly constant plasma concentrations. This may or may not lead to side effects.
The sustained release formulations of the invention have the benefit of providing an extended therapeutic benefit reduced side effects relative to other dosage forms and other dosing regimens. The sustained release formulations of the invention are also able to provide the benefit of an extended dosing interval. This means that a patient can be dosed only once a day instead of twice or three times per day.
As used herein, the term intra granular refers to components or blend of a composition which is to be granulated with binder solution by wet granulation method. It comprises all components added in to the blend before granulation.
As used herein, the term “extra granular” refers to those components of a composition of the present invention that are outside of the granules. During manufacturing, the extra granular fraction includes the ingredients or inactive excipients that are added to the intra granular fraction post drying.
As used herein, the term “film coating” refers to thin polymer based coat applied to a solid dosage form.
The term “polymer” refers to a chemical compound or mixture of compounds consisting of repeating structural units created through a process of polymerization. Suitable polymers useful in this invention are described throughout.
As used herein, the term “% w/w” as used herein refers to the weight of a component based on the total weight of a final composition. As per present invention, % w/w to be calculated against final composition i.e film coated composition.
The term about, is used herein to indicate variability of + 5% surrounding the designated value.
The term inactive excipient means a pharmacologically inactive component such as a diluent, binder, disintegrant, glidant, surfactant, wetting agent, lubricant, solubilizer, stabilizer sweetener, flavoring agent, plasticizer, coloring agent and the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for human pharmaceutical use. For present invention inactive excipients for core may be selected from diluent, lubricant and glidant and for coating, inactive excipients may be selected from plasticizer, opacifier and coloring agent.
The main embodiment of the present invention is sustained release oral pharmaceutical composition comprising
a. a core comprising 80 % to 95 % w/w of dicycloverine or a salt thereof, one or more binder, one polymer present intra granular and one polymer present extra granular and one or more inactive excipients,
b. film coating over core comprising 5% to 20% w/w of dicycloverine or a salt thereof, water soluble film forming polymer and one or more inactive excipients.
Preferably, the pharmaceutical composition refers to tablets or capsules. More preferably, the pharmaceutical composition refers to sustained release oral tablets, which may be uncoated or film coated. More preferably, the composition is film coated sustained release tablets.
The term “composition” and “formulation” as used herein conveys the same meaning and can be used interchangeably.
The composition preferably features a core, over which an outer coating is layered. The term “core” is hereinafter defined as an uncoated tablet.
Preferably, the dicycloverine present in the composition of present invention is in the form its hydrochloride salt and in the whole specification whenever dicycloverine is used, it means dicycloverine hydrochloride.
In a preferred embodiment, core comprises 80 % to 95 % w/w of dicycloverine or a salt thereof and coating comprises 5% to 20% w/w of dicycloverine or a salt thereof. In a more preferred embodiment, core comprises 85 % to 95 % w/w of dicycloverine or a salt thereof and coating comprises 5% to 15% w/w of dicycloverine or a salt thereof. In a most preferred embodiment, core comprises about 90% w/w of dicycloverine or a salt thereof and coating comprises about 10% w/w of dicycloverine or a salt thereof.
In a preferred embodiment, polymer is either hydrophilic polymer or hydrophobic polymer.
In one preferred embodiment, intra granular polymer is hydrophilic and extra granular polymer is hydrophobic.
In one preferred embodiment, intra granular polymer is hydrophilic and extra granular polymer is hydrophobic.
In one preferred embodiment, intra granular polymer is hydrophobic and extra granular polymer is hydrophilic.
In one preferred embodiment, both intra granular polymer and extra granular polymer is hydrophilic.
In another preferred embodiment, both intra granular polymer and extra granular polymer is hydrophobic.
Hydrophilic polymer required for sustaining the release of dicycloverine as per present invention is selected from the group consisting of methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, alginic acid, carbomer, gelatin and polyethylene oxide. Preferably, the hydrophilic polymer is a hypromellose (hydroxypropyl methylcellulose or HPMC), such as, for example, (a) hypromellose (METHOCEL™ K4M), hypromellose (METHOCEL™ K15M) and/or (c) hypromellose (METHOCEL™ K100M) alone or in combination.
As per one preferred embodiment, intra granular polymer is present in the range from 15 to 40% w/w and extra granular polymer is present in the range from 5 to 25% w/w. As per more preferred embodiment, intra granular polymer is present in the range from 20 to 35% w/w and extra granular polymer is present in the range from 10 to 20% w/w.
The drug release is controlled by the thickness of the gel, diffusion through the gel, and erosion of the gel. The common method of using such hydrophilic polymer is to incorporate them as dry with direct compression process or can be added intra granular with wet granulation process. As per preferred embodiment, wet granulation method can be used.
Hydrophobic polymer required for sustaining the release of dicycloverine as per present invention is selected from the group consisting of ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, castrowax, camaubawax, glycerol monostearate stearylalcohol, hydrophobic polyacrylamide derivative and hydrophobic methacrylic acid derivative.
In a preferred embodiment, one hydrophilic polymer is present intra granular and to be mixed with dicycloverine and other inactive excipients and one hydrophilic polymer is to be added extra granularly with dried granules along with other inactive excipients.
As per one embodiment, binder is selected from but are not limited to, starches such as potato starch, wheat starch, maize starch; celluloses such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth or combinations thereof. In a preferred embodiment, binder may be dry binder or in the form binder solution form, preferably in the form of binder solution. In a preferred embodiment, binder for present invention is maize starch or hydroxypropylmethyl cellulose of low viscosity grade like E6 Premium LV or combinations thereof. In a preferred embodiment, binder can be used in the range from 2 % to 25% w/w. In a more preferred embodiment, binder is used in the range from 10 to 20% w/w.
As per one embodiment, binder solution is prepared by adding binder in aqueous or hydroalcoholic solvent, preferably aqueous using water. As per one embodiment, binder is added as dry binder. As per one more preferred embodiment, composition of present invention uses dry binder as well as binder solution both.
For present invention, one or more inactive excipients for core may be selected from diluent, lubricant and glidant.
Diluents for the present invention may be selected from cellulose-derived materials such as powdered cellulose, macrocrystalline cellulose, microfine cellulose, and the like; lactose, starch, pregelatinized starch, sugars and sugar alcohols such as mannitol, sorbitol, erythritol and the like; dextrates, dextrin, dextrose, inorganic diluents like calcium carbonate, calcium sulphate, dibasic calcium phosphate and its hydrate, tribasic calcium phosphate and its hydrate, magnesium carbonate, magnesium oxide, potassium chloride, sodium chloride or mixture of one or more of such diluent. Particularly suitable diluents are microcrystalline cellulose, dibasic calcium phosphate dihydrate or mixture thereof. More preferably, the diluent is microcrystalline cellulose. The diluent may be present in an amount ranging from about 5 % to about 25 % w/w of the composition.
Glidants for the present invention may be used include talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch and tribasic calcium phosphate. The glidant may be present in an amount ranging from 0.5 % to 4 % w/w of the composition.
Lubricants for the present invention may be selected from magnesium stearate, calcium stearate, hydrogenated castor oil, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, leucine, mineral oil, light mineral oil, myristic acid, palmitic acid, polyethylene glycol, potassium-benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, hydrogenated vegetable oil, zinc stearate, magnesium lauryl sulphate, sodium stearyl fumarate, polyethylene glycol, stearic acid, colloidal silicon dioxide or mixtures thereof. Preferred lubricant is magnesium stearate. The lubricant may be present in an amount ranging from 0.5 % to 3 % w/w of the composition.
It would be appreciated that a person skilled in the art is cognizant of the fact that certain excipients can be used both as a lubricant and glidant.
As per one preferred embodiment, the oral pharmaceutical composition is in the form of tablet with film coating. The core is prepared by adding dicycloverine or salts thereof, binder, a polymer and one or more inactive excipients and mixing followed by granulating with binder solution followed by drying wet mass followed by mixing dried granules with a polymer and one or more inactive excipients followed by compressing to form uncoated tablet or core.
The compressed uncoated tablets are further film coated. Film coating is done either by nonaqueous coating or aqueous coating or by hydroalcoholic coating. This coating composition contains water soluble film forming polymer such as hydroxypropyl methyl cellulose (hypromellose), hydroxyl propyl cellulose, methyl cellulose, polyvinyl alcohol; solvents, colloidal silicon dioxide, optionally other excipients such as plasticizers, lubricants and colourants. A preferred blend of hydroxypropyl methylcellulose, a plasticizer and a colorant is commercially available under the trade name Opadry®.
Solvents used for coating can be either aqueous or non-aqueous solvents. Suitable non-aqueous solvents include, but are not limited to isopropyl alcohol, ethanol, dichloromethane, acetone and the like. Aqueous solvent include water. In a preferred embodiment, aqueous coating composition is used.
Plasticizer of the present invention may be selected from the group comprising phthalate esters, phosphate esters, and other esters like citrates, stearates, sebacate, oleate, oils, glycerols, glycols etc. Preferably, the plasticizer of the present invention is selected from the group comprising polyethylene glycol, ethyl phthalate, methyl phthalate, propylene glycol, fractionated coconut oil, lecithin, castor oil, dibutylsebacate, diethyl phthalate, dipropyl phthalate, dibutyl phthalate, triacetin, liquid paraffin, triethyl citrate, and combinations thereof.
Opacifiers of the present invention may be selected from the group comprising titanium dioxide, zinc oxide, calcium carbonate, magnesium oxide and the like.
Coloring agent of the present invention may include iron oxide colors, Lake or soluble colors, natural colors, candurin colors and the like or any food approved colors or dyes or combinations thereof.
As per one embodiment, the present invention provides a process for preparing sustained release oral pharmaceutical composition comprising steps of;
a) Mixing dicycloverine hydrochloride and a polymer,
b) Preparing binder solution comprising a binder and water,
c) Granulating blend of step a) with binder solution of step b),
d) Drying granulated wet mass of step c),
e) Mixing dried granules of step d) with a polymer and one or more inactive excipients,
f) Compressing blend of step e) in to tablets,
g) Preparing film coating solution comprising a film forming polymer, dicycloverine hydrochloride and one or more inactive excipients and
h) Coating tablets of step f) with film coating dispersion prepared in step g).
As per one embodiment, the oral pharmaceutical composition of dicycloverine or salts thereof to be used for treating functional conditions involving smooth muscle spasm like functional bowel/irritable bowel syndrome.
The sustained release oral pharmaceutical composition of dicycloverine, preferably dicycloverine hydrochloride of the present invention exhibits advantages like release of drugs for longer period to make it eligible for once daily dosing.
The dissolution of sustained release tablet composition of present invention is measured as per dissolution test and able to sustain up to at least 16 hours as can be seen from the following examples.
Dissolution test parameters performed on sustained release tablets of present invention is as below;
Dissolution media: 0.1 N HC1
Apparatus: Paddle
Speed: 75 RPM
Volume: 900ml
Time point: lhr, 6 hr, 12 hr, 16 hr
As per one embodiment, the sustained release tablets of dicycloverine hydrochloride of present invention provides dissolution profile as per below ranges when performed as per above provided dissolution parameters:
| Time (hr) | % drug dissolved |
| 1 | 20-30 |
| 3 | 25-45 |
| 6 | 40-60 |
| 9 | 50-70 |
| 12 | 65-85 |
| 16 | not less than 85 |
The sustained release composition of present invention is analysed for related substance as per below analytical method and parameters;
Method: Thin layer chromatography (TLC)
Mobile phase: 70 volume of N-hexane, 30 volume of 1-propanol, 1ml ammonia and 0.5 ml glacial acetic acid
Spraying agent:
1) Potassium iodobismuthate solution Rl: Dissolve 100 gm of (+) tartric acid in 400 ml of water and add 8.5 gm of bismuth oxynitrate. Sahke for 1 hour, add 200 ml of a 40% w/v solution of potassium iodide an dshake well. Allow to stand for 24 hour and filter.
2) Potassium iodobismuthate solution, Dilute: Dissolve 100 gm of (+) tartric acid in 500 ml of water and add 50 ml of potassium iodobismuthate solution Rl.
Procedure: Separately inject injections of SST, sample solution, standard solution and placebo in to TLC plate and record it.
The sustained release tablets of different composition prepared as per present invention and out of many batches, few selected batches with satisfactory parameters were further evaluated for stability at different conditions like 40°C/75%RH, 30°C/65%RH and 25°C/60%RH.
The following examples are illustrative of the present invention, and the examples should not be considered as limiting the scope of this invention in any way, as these examples and other equivalents thereof will become apparent to those versed in the art, in the light of the present disclosure, and the accompanying claims.
Examples
Example 1: Sustained release tablet of 30 mg and 60 mg dicycloverine hydrochloride with hydrophilic polymer intra granular and hydrophilic polymer extra granular
| Ingredient | Mg/tablet | Mg/tablet |
| Dry mixing |
| Dicycloverine Hydrochloride | 54 | 27 |
| Hydroxypropylmethyl cellulose (HPMC) K15M | 75 | 75 |
| Micro crystalline cellulose (MCC PH 101) | 33 | 33 |
| Maize Starch | 27.5 | 27.5 |
| Binding |
| Hydroxypropylmethyl cellulose (HPMC) E6 | 10 | 10 |
| Purified water | q.s. | q.s. |
| Blending & Lubrication |
| Hydroxypropylmethyl cellulose (HPMC) KI00M | 45 | 45 |
| Aerosil | 6.75 | 6.75 |
| Magnesium stearate | 3.75 | 3.75 |
| Core Weight | 255 | 228 |
| Coating |
| Dicycloverine Hydrochloride | 6 | 3 |
| Opadry# | 7.2 | 7.2 |
| Final Coated Tablet Weight | 268.20 | 238.20 |
| #Opadry composition: Hypromellose 6 Cps, PEG 400, TiO2 and ' | 'ale |
Procedure:
1. Sifting and dry mixing: Sift Dicycloverine hydrochloride, Hydroxypropylmethyl cellulose K15M, MCC PH 101 and maize starch through 30 #sieve individually and mix it in RMG.
2. Binder solution preparation: Add HPMC E6 into water under continuous stirring until clear solution obtained
3. Mass Binding: Bind the Blend of step-1 using binder solution of step-2 in RMG.
4. Drying: Dry the wet mass of step-3 in FBD to achieve desired LOD.
5. Sifting: Sift dried granules of step-4 through 20# sieve.
6. Blending: Sift HPMC KI00M DC2 and Aerosil through 40# sieve and mix with granules of step-5.
7. Lubrication: Sift Magnesium stearate through 60# sieve and mix with granules of step-6.
8. Compress the lubricated blend of step-7 using appropriate punch tooling.
9. Coating: Prepare coating dispersion by initially dissolving dicycloverine hydrochloride in water and adding Opadry under continuous stirring for 45 mins.
10. Perform coating of the tablets as per desired weight gain.
Example 2: Sustained release tablet of 30 mg and 60 mg dicycloverine hydrochloride with intra granular hydrophobic polymer and hydrophilic polymer extra granular
| Ingredient | Mg/tablet | Mg/tablet |
| Dry mixing |
| Dicycloverine Hydrochloride | 54 | 27 |
| Ethylcellulose | 75 | 75 |
| Micro crystalline cellulose (MCC PH 101) | 33 | 33 |
| Maize Starch | 27.5 | 27.5 |
| Binding |
| Hydroxypropylmethyl cellulose (HPMC) E6 | 10 | 10 |
| Purified water | q.s. | q.s. |
| Blending & Lubrication |
| Hydroxypropylmethyl cellulose (HPMC) KI OOM | 45 | 45 |
| Aerosil | 6.75 | 6.75 |
| Magnesium stearate | 3.75 | 3.75 |
| Core Weight | 255 | 228 |
| Coating |
| Dicycloverine Hydrochloride | 6 | 3 |
| Opadry# | 7.2 | 7.2 |
| Final Coated Tablet Weight | 268.20 | 238.20 |
| #Opadry composition: Hypromellose 6 Cps, PEG 400, TiO2 andr. | 'ale |
Procedure: As per Example 1
Dissolution result of Example 2
| Time (hr) | % Drug dissolved |
| 1 | 25.3 |
| 6 | 66.8 |
| 12 | 90.4 |
| 16 | 101.4 |
Example 3: Sustained release tablet of 30 mg and 60 mg dicycloverine hydrochloride with intra granular hydrophilic polymer and hydrophobic polymer extra granular
| Ingredient | Mg/tablet | Mg/tablet |
| Dry mixing |
| Dicycloverine Hydrochloride | 54 | 27 |
| Hydroxypropylmethyl cellulose (HPMC) K15M | 75 | 75 |
| Micro crystalline cellulose (MCC PH 101) | 33 | 33 |
| Maize Starch | 27.5 | 27.5 |
| Binding |
| Hydroxypropylmethyl cellulose (HPMC) E6 | 10 | 10 |
| Purified water | q.s. | q.s. |
| Blending & Lubrication |
| Ethylcellulose | 45 | 45 |
| Aerosil | 6.75 | 6.75 |
| Magnesium stearate | 3.75 | 3.75 |
| Core Weight | 255 | 228 |
| Coating |
| Dicycloverine Hydrochloride | 6 | 3 |
| Opadry# | 7.2 | 7.2 |
| Final Coated Tablet Weight | 268.20 | 238.20 |
| #Opadry composition: Hypromellose 6 Cps, PEG 400, TiO2 anc | Talc |
Procedure: As per Example 1
Dissolution result of Example 3
| Time (hr) | % Drug dissolved |
| 1 | 24.7 |
| 6 | 62.4 |
| 12 | 88.6 |
| 16 | 98.3 |
Example 4: Sustained release tablet of 30 mg and 60 mg dicycloverine hydrochloride with hydrophilic polymer intra granular and hydrophilic polymer extra granular without 10 maize starch
| Ingredient | Mg/tablet | Mg/tablet |
| Dry mixing | |
| Dicycloverine Hydrochloride | 54 | 27 |
| Hydroxypropylmethyl cellulose (HPMC) K15M | 75 | 75 |
| Micro crystalline cellulose (MCC PH 101) | 60.5 | 60.5 |
| Binding | |
| Hydroxypropylmethyl cellulose (HPMC) E6 | 10 | 10 |
| Purified water | q.s | q.s |
| Blending & Lubrication | |
| Hydroxypropylmethyl cellulose (HPMC) KI OOM | 45 | 45 |
| Aerosil | 6.75 | 6.75 |
| Magnesium stearate | 3.75 | 3.75 |
| Core Weight | 255 | 228 |
| Coating | |
| Dicycloverine Hydrochloride | 6 | 3 |
| Opadry# | 7.2 | 7.2 |
| Final Coated Tablet Weight | 268.20 | 238.20 |
| #Opadry composition: Hypromellose 6 Cps, PEG 400, TiO2 andr | ale |
Procedure: As per Example 1
Dissolution result of Example 4
| Time (hr) | % Drug dissolved |
| 1 | 22.8 |
| 6 | 53.5 |
| 12 | 77.1 |
| 16 | 87.0 |
Example 5: Sustained release tablet of 30 mg and 60 mg dicycloverine hydrochloride with hydrophobic polymer intra granular and hydrophobic polymer extra granular
| Ingredient | Mg/tablet | Mg/tablet |
| Dry mixing |
| Dicycloverine Hydrochloride | 54 | 27 |
| Ethylcellulose | 75 | 75 |
| Micro crystalline cellulose (MCC PH 101) | 33 | 33 |
| Maize starch | 27.5 | 27.5 |
| Binding |
| Hydroxypropylmethyl cellulose (HPMC) E6 | 10 | 10 |
| Purified water | q.s | q.s |
| Blending & Lubrication |
| Ethylcellulose | 45 | 45 |
| Aerosil | 6.75 | 6.75 |
| Magnesium stearate | 3.75 | 3.75 |
| Core Weight | 255 | 228 |
| Coating |
| Dicycloverine Hydrochloride | 6 | 3 |
| Opadry# | 7.2 | 7.2 |
| Final Coated Tablet Weight | 268.20 | 238.20 |
| #Opadry composition: Hypromellose 6 Cps, PEG 400, TiO2 and Ί | 'ale |
Procedure: As per Example 1
Dissolution result of Example 5
| Time (hr) | % Drug dissolved |
| 1 | 20.1 |
| 6 | 32.5 |
| 12 | 87.4 |
| 16 | 91.5 |
Example 6: Stability studies
Based on satisfactory dissolution result, Example 1 was selected for performing stability study.
Stability study of composition of Example 1 was performed at different temperature and relative humidity conditions for 3 months and results are as described below;
Stability result of tablet composition as prepared in Example 1 (30 mg strength)
| Time/Parameter/Temp condition | Description | Water by KF/LOD(%) | Assay(%) | Dissolution(%) | Related substances |
| Initial | White to off white round shapedbiconvex film coated | 5.60 | 101.95 | 1 Hr: 26.26 Hr: 61.612 Hr: 84.4 | Complies |
| tablet debossed with ‘D 2’ on one side and plain on the other side. | | | 16 Hr: 95.6 | |
| 30 days(40°C/75%RH) | White to off white round shapedbiconvex film coated tablet debossed with ‘D 2’ on one side and plain on the other side. | 6.40 | 101.90 | 1 Hr: 25.96 Hr: 62.212 Hr: 82.416 Hr: 89.8 | Complies |
| 60 days(40°C/75%RH) | White to off white round shapedbiconvex film coated tablet debossed with ‘D 2’ on one side and plain on the other side. | 6.80 | 101.60 | 1 Hr: 25.96 Hr: 61.212 Hr: 83.716 Hr: 92.3 | Complies |
| 90 days(40°C/75%RH) | White to off white round shapedbiconvex film coated tablet debossed with ‘D 2’ on one side and plain on the other side. | 7.25 | 102.20 | 1 Hr: 24.86 Hr: 58.7412 Hr: 81.716 Hr: 90.5 | Complies |
| | | | | |
| 30 days(30°C/65%RH) | White to off white round shapedbiconvex film coated tablet debossed with ‘D 2’ on one side and plain on the other side. | 6.42 | 102.10 | 1 Hr: 24.66 Hr: 57.512 Hr: 81.116 Hr: 92.4 | Complies |
| | | | | |
| 30 days(25°C/60%RH) | White to off white round shapedbiconvex film coated tablet debossed with ‘D 2’ on one side and plain on the other side. | 6.45 | 99.40 | 1 Hr: 25.96 Hr: 62.212 Hr: 82.416 Hr: 92.4 | Complies |
Stability result of tablet composition as prepared in Example 1 (60 mg strength)
| Time/Parameter/Temp condition | Description | Water by KF/LOD(%) | Assay(%) | Dissolution(%) | Related substance |
| Initial | White to off white round shapedbiconvex film coated tablet debossed with ‘D 2’ on one side and plain on the other side. | 5.16 | 101.25 | 1 Hr: 24.76 Hr: 59.812 Hr: 84.516 Hr: 96.4 | Complies |
| 30 days(40°C/75%RH) | White to off white round shapedbiconvex film coated tablet debossed with ‘D 2’ on one side and plain on the other side. | 6.20 | 102.10 | 1 Hr: 23.36 Hr: 56.612 Hr: 80.016 Hr: 91.0 | Complies |
| 60 days(40°C/75%RH) | White to off white round shapedbiconvex film coated tablet debossed with ‘D 2’ on one side and | 9.70 | 99.20 | 1 Hr: 23.66 Hr: 57.312 Hr: 80.716 Hr: 91.2 | Complies |
| plain on the other side. | | | | |
| 90 days(40°C/75%RH) | White to off white round shapedbiconvex film coated tablet debossed with ‘D 2’ on one side and plain on the other side. | 7.11 | 99.90 | 1 Hr: 23.56 Hr: 56.712 Hr: 78.316 Hr: 90.6 | Complies |
| | | | | |
| 30 days(30°C/65%RH) | White to off white round shapedbiconvex film coated tablet debossed with ‘D 2’ on one side and plain on the other side. | 6.80 | 100.7 | 1 Hr: 23.76 Hr: 56.612 Hr: 81.316 Hr: 92.0 | Complies |
| | | | | |
| 30 days(25°C/60%RH) | White to off white round shapedbiconvex film coated tablet debossed with ‘D 2’ on one side and plain on the other side. | 5.60 | 100.4 | 1 Hr: 24.46 Hr: 58.212 Hr: 82.116 Hr: 93.7 | Complies |
Claims