WO2023095183A1

WO2023095183A1 - A pharmaceutical composition and a solid dosage form thereof

Info

Publication number: WO2023095183A1
Application number: PCT/JO2021/050017
Authority: WO
Inventors: Wasfy OBEIDAT; Abdolelah JARADAT
Original assignee: Jordan University Of Science And Technology
Priority date: 2021-11-24
Filing date: 2021-11-24
Publication date: 2023-06-01

Abstract

The present disclosure provides a pharmaceutical composition including at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material, at least one non-swelling pH dependent enteric release retardant, at least one non-swelling pH dependent non-enteric release retardant, and at least one pH dependent release retardant hydrogel, and a pharmaceutically acceptable carrier/excipient. The present disclosure further provides a solid oral dosage form including the pharmaceutical composition in a sustained/controlled release formulation.

Description

A PHARMACEUTICAL COMPOSITION AND A SOLID DOSAGE FORM THEREOF

TECHNICAL FIELD

[01] The present disclosure related to pharmaceutical compositions and sustained release formulations thereof, and more particularly to pharmaceutical compositions containing weakly acidic or neutral pharmaceutically active ingredients and sustained release oral formulations thereof.

BACKGROUND

[02] Sustained and controlled release formulations of a given pharmaceutical preparation provide the ability of this preparation to maintain a desired therapeutic effect over a relatively longer period of time compared to immediate release preparations. Moreover, for drugs having a short elimination half-life, less frequent administration and better patient compliance may be obtained with sustained release preparations as compared to the immediate release or conventional dosage forms.

[03] Therefore, prior art solutions tried to provide sustained and controlled release formulations of pharmaceutical preparations. For instance, a study published in 2020 by Wasfi M Obeidat et al. evaluated the suitability of a ternary mixture of polymers comprised of Eudragit® El 00, Eudragit®L100, and sodium alginate to serve as a carrier for sustained drug release for weakly basic pharmaceutically active ingredients, such as Metronidazole.

[04] The United States patent number 6083532 discloses a formulation and a matrix tablet dosage form for sustained release, the matrix tablet includes three polymers, namely are Eudragit® LI 00 or SI 00 and alginate and hydroxyl propyl methyl cellulose or propylene oxide. Eudragit® LI 00 or SI 00 are pH dependent and have enteric properties. However, hydroxyl propyl methyl cellulose or propylene oxide is pH independent and works in acidic and alkaline as well as neutral media in similar pattern.

[05] Another study published in 2015 by Wasfi M Obeidat et al. investigated the influence of Eudragit®E100 polymer in modifying the release rates and compaction properties of water soluble pharmaceutically active ingredient, paracetamol, from Carbopol® 97 IP NF polymer matrix tablets prepared by direct compression.

SUMMARY

[06] It is an object of the preset disclosure to provide a pharmaceutical composition including at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material, at least one non-swelling pH dependent enteric release retardant, at least one non-swelling pH dependent non-enteric release retardant, at least on pH dependent release retardant hydrogel, and a pharmaceutically acceptable carrier/excipient.

[07] In aspects of the present disclosure, the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material may be selected from a group of agents including analgesics, antipyretics, anti-inflammatory agents, antidepressants, anti-asthma agents, antibiotics, antivirals, antifungals, anticonvulsants, antidiabetics, anti-gout agents, antihistamines and anti-allergy agents, antihypertensives, anti-migraine agents, anti- muscarinics, antinauseants, antineoplastics, antipsoriatics, antispasmodics and motility agents, antithrombotics, bone modulating agents, bronchodilators, cardiovascular drugs, diuretics, diagnostic agents, dopaminergics, anxiolytics, sedatives, hypnotics and antipsychotics, immunomodulators, lipid regulating agents, muscle relaxants, nutritional supplements, sedatives, thyroid agents, uricosurics, vasodilators, vitamins, or combinations thereof.

[08] In some aspects of the present disclosure, the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material may include acetyl salicylic acid, diclofenac, fenoprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, naproxen, piroxicam, sulindac, rofecoxib, penicillins, cephalosporins, quinolones, tetracyclines and sulphonamides, trimethoprim, temazepam and flunitrazepam, barbiturates, pamidronic acid, risedronic acid and zoledronic acid, atorvastin, simvastatin, cerivastin, fluvastin, pravastatin, clofibrate, bezafibrate, gemfibrozil, ascorbic acid, captopril, chlorambucil, cyclophosphamide, fluoxetine, norfluoxetine, folic acid, furosemide, fusidic acid, glibenclamide, gliclazide, glutethimide, isoniazid, levodopa, methotrexate, methyldopa, montelukast, nalidixic acid, phenacetin, phenindione, probenecid, rifampicin, sulphasalazine, sulphinpyrazone, thyroxine, tolazamide, tolbutamide, valproic acid, warfarin, sodium cromoglycate, fenoterol, salbutamol, theophylline, aminophylline, zafirlukast, betamethasone, dexamethasone, triamcinolone, prednisolone, prednisone or a pharmaceutically acceptable salt, solvate, polymorph, ester thereof, and combinations thereof.

[09] In other aspects, the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material may be ibuprofen.

[010] In yet other aspects, the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material may be paracetamol, hyrocodone, oxycodone, the triptans including eletriptan, rizatriptan, zolmitriptan; the benzodiazepines including diazepam, flurazepam, flunitrazepam, temazepam, alprazolam, lorazepam, fexofenadine, metoclopramide, loperamide, zolpidem, zopiclone, loratadine, ondansetron, granisetron, tadalafil, vardenafil, sildenafil, ranitidine, famotidine, codeine, fentanyl, tramadol, pseudoephedrine, phenylpropanolamine, dextromethorphan, chlorpheniramine, diphenhydramine, cetirizine, cimetidine, pharmaceutically acceptable salts thereof, or combinations thereof.

[Oil] In yet other aspects, the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material may be paracetamol.

[012] In aspects of the present disclosure, the at least one non-swelling pH dependent enteric release retardant may be selected from a group including polymethacrylic acid derivatives, cellulose derivatives, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate, cellulose benzoate phthalate, cellulose propionate phthalate, or combinations thereof.

[013] In some aspects, the at least one non-swelling pH dependent enteric release retardant may be selected from a group including acrylic copolymer based pH dependent release retardant include acrylic acid copolymer, methyl acrylate acrylic acid copolymer, methyl acrylate methacrylic acid copolymer, butyl acrylate acrylic acid copolymer, methacrylic acid methyl methacrylate copolymer, methacrylic acid ethyl acrylate copolymer, methyl acrylate methacrylic acid octyl acrylate copolymer, or combinations thereof. [014] In aspects of the present disclosure, the at least one non-swelling pH dependent enteric release retardant may include methacrylic acid methyl methacrylate copolymer, methacrylic acid ethyl acrylate copolymer, or combinations thereof.

[015] In some aspects, the pharmaceutical composition may include methacrylic acid methyl methacrylate copolymer and methacrylic acid ethyl acrylate copolymer at a ratio of 5: 1 by weight.

[016] In other aspects, the pharmaceutical composition may include methacrylic acid methyl methacrylate copolymer and methacrylic acid ethyl acrylate copolymer at a ratio of 3 : 1 by weight.

[017] In yet other aspects, the pharmaceutical composition may include methacrylic acid methyl methacrylate copolymer and methacrylic acid ethyl acrylate copolymer at a ratio of 1 : 1 by weight.

[018] In aspects of the present disclosure, the at least one non-swelling pH dependent non-enteric release retardant may be selected from a group including polymer based on dimethylaminoethyl methacrylate, neutral methacrylic acid esters, or combinations thereof.

[019] In aspects of the present disclosure, the at least on pH dependent release retardant hydrogel may include alginic acid, or a pharmaceutically acceptable salt thereof.

[020] In some aspects, the at least on pH dependent release retardant hydrogel may be sodium alginate.

[021] In some aspects, the pharmaceutical composition may include from about 5% to about 90% by weight of the least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material.

[022] In other aspects, the pharmaceutical composition may include from about 1% to about 35% by weight of the at least one non-swelling pH dependent enteric polymer.

[023] In yet other aspects, the pharmaceutical composition may include from about 5% to about 25% by weight of the at least one non-swelling pH dependent enteric polymer. [024] In some aspects, the pharmaceutical composition may include from about 1% to about 35% by weight of the at least one non-swelling pH dependent non-enteric polymer.

[025] In other aspects, the pharmaceutical composition may include from about 5% to about 25% by weight of the at least one non-swelling pH dependent non-enteric polymer.

[026] In yet other aspects, the pharmaceutical composition may include from about 5% to about 50% by weight of the at least one pH dependent release retardant hydrogel.

[027] In some aspects, the pharmaceutical composition may include from about 10% to about 25% by weight of the at least one pH dependent release retardant hydrogel.

[028] In some aspects, the pharmaceutical composition may include the at least one pH dependent release retardant hydrogel, the at least one at least one non-swelling pH dependent enteric release retardant and the at least one non-swelling pH dependent non-enteric release retardant at a ratio of 3: 1 by weight.

[029] In other aspects, the pharmaceutical composition may include the at least one pH dependent release retardant hydrogel, the at least one at least one non-swelling pH dependent enteric release retardant and the at least one non-swelling pH dependent non-enteric release retardant at a ratio of 2: 1 by weight.

[030] In yet other aspects, the pharmaceutical composition may include the at least one pH dependent release retardant hydrogel, the at least one at least one non-swelling pH dependent enteric release retardant and the at least one non-swelling pH dependent non-enteric release retardant at a ratio of 1 : 1 by weight.

[031] In aspects of the present disclosure, the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material may have a size ranging from about 1 micron to about 800 microns.

[032] In some aspects, the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material may have a size ranging from about 50 microns to about 500 microns. [033] In other aspects, the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material may have a size ranging from about 50 microns to about 250 microns.

[034] In aspects of the present disclosure, the at least one non-swelling pH dependent enteric release retardant may have a size ranging from about 1 micron to about 800 microns.

[035] In some aspects, the at least one non-swelling pH dependent enteric release retardant may have a size ranging from about 50 microns to about 500 microns.

[036] In other aspects, the at least one non-swelling pH dependent enteric release retardant may have a size ranging from about 50 microns to about 150 microns.

[037] In aspects of the present disclosure, the at least one non-swelling pH dependent non-enteric release retardant may have a size ranging from about 1 micron to about 800 microns.

[038] In some aspects, at least one non-swelling pH dependent non-enteric release retardant may have a size ranging from about 50 microns to about 500 microns.

[039] In other aspects, the at least one non-swelling pH dependent non-enteric release retardant has a size ranging from about 50 microns to about 150 microns.

[040] In aspects of the present disclosure, the at least one pH dependent release retardant hydrogel may have a size ranging from about 1 micron to about 800 microns.

[041] In some aspects, the at least one pH dependent release retardant hydrogel may have a size ranging from about 50 microns to about 500 microns.

[042] In other aspects, the at least one pH dependent release retardant hydrogel may have a size ranging from about 50 microns to about 150 microns.

[043] Other aspects of the present disclosure provide a solid oral dosage form including the pharmaceutical composition as described herein, wherein the solid oral dosage form may be a matrix tablet for sustained or controlled release. [044] In some aspects, the matrix tablet may be prepared by direct compression, dry granulation, or molding.

[045] In some aspects, the dosage form may release about 50% by weight or more of an at least weakly acidic, base salt, or neutral pharmaceutically active material within 12 hours from administration.

[046] In other aspects, the dosage form may release about 80% by weight or more of an at least weakly acidic, base salt, or neutral pharmaceutically active material within 24 hours from administration.

BRIEF DESCRIPTION OF THE DRAWINGS

[047] The present disclosure will now be described with reference to the accompanying drawings, which illustrate embodiments of the present disclosure, without however limiting the scope of protection thereto, and in which:

[048] FIG. 1 illustrates a line chart showing dissolution profiles of a first exemplary model pharmaceutically active material using different concentrations of matrix polymers in the solid oral dosage form prepared in accordance with embodiments of the present disclosure.

[049] FIG. 2 illustrates a line chart showing the dissolution profile of a second exemplary model pharmaceutically active material at different concentrations of matrix polymers in the solid oral dosage form prepared in accordance with embodiments of the present disclosure.

[050] FIG. 3 illustrates a line chart showing the dissolution profile of a second exemplary model pharmaceutically active material at different concentrations of matrix polymers in the solid oral dosage form prepared in accordance with embodiments of the present disclosure and the dissolution profile of the second exemplary pharmaceutically active material in the dosage form available in the market.

DETAILED DESCRIPTION

[051] The term “pharmaceutically acceptable carrier/excipient”, as used herein, means a nontoxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; binding agents such as hypromellose; disintegrating agents such as crosscarmellose; water; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil; cottonseed oil; safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgement of the formulator.

[052] All components of the pharmaceutical composition have to be pharmaceutically acceptable. The term "pharmaceutically acceptable" means at least non-toxic. The therapeutically active component should preferably be present in the above-mentioned pharmaceutical composition, the concentration of about 0.1 to 99.5% by weight, preferably of about 0.5 to 95% by weight of the total mixture.

[053] As used herein, the term “non-swelling” refers to any excipient that does not swell in water or swells only moderately in water.

[054] As used herein, the term “release retardant” refers to any excipient that can retard the release of a pharmaceutically active material, including, but not limited to, polymers, waxes, and fatty acids.

[055] As used herein, the term “pH dependent release retardant” refers to any excipient that can retard the release of a pharmaceutically active material which has pH dependent solubility, thus its performance is dependent on the pH of the environment encountering it.

[056] Embodiments of the present disclosure provide a pharmaceutical composition including at least one weakly acidic, salt of a weak base, or a neutral pharmaceutically active material, at least one non-swelling pH dependent enteric release retardant, at least one non-swelling pH dependent non-enteric release retardant, at least on pH dependent release retardant hydrogel, and a pharmaceutically acceptable carrier/excipient.

[057] In embodiments of the present disclosure, the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material may be selected from a group of agents including analgesics, antipyretics, anti-inflammatory agents, antidepressants, anti-asthma agents, antibiotics, antivirals, antifungals, anticonvulsants, antidiabetics, anti-gout agents, antihistamines and anti-allergy agents, antihypertensives, anti-migraine agents, anti- muscarinics, antinauseants, antineoplastics, antipsoriatics, antispasmodics and motility agents, antithrombotics, bone modulating agents, bronchodilators, cardiovascular drugs, diuretics, diagnostic agents, dopaminergics, anxiolytics, sedatives, hypnotics and antipsychotics, immunomodulators, lipid regulating agents, muscle relaxants, nutritional supplements, sedatives, thyroid agents, uricosurics, vasodilators, vitamins, or combinations thereof.

[058] In some embodiments of the present disclosure, the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material may include acetyl salicylic acid, diclofenac, fenoprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, naproxen, piroxicam, sulindac, rofecoxib, penicillins, cephalosporins, quinolones, tetracyclines and sulphonamides, trimethoprim, temazepam and flunitrazepam, barbiturates, pamidronic acid, risedronic acid and zoledronic acid, atorvastin, simvastatin, cerivastin, fluvastin, pravastatin, clofibrate, bezafibrate, gemfibrozil, ascorbic acid, captopril, chlorambucil, cyclophosphamide, fluoxetine, norfluoxetine, folic acid, furosemide, fusidic acid, glibenclamide, gliclazide, glutethimide, isoniazid, levodopa, methotrexate, methyldopa, montelukast, nalidixic acid, phenacetin, phenindione, probenecid, rifampicin, sulphasalazine, sulphinpyrazone, thyroxine, tolazamide, tolbutamide, valproic acid, warfarin, sodium cromoglycate, fenoterol, salbutamol, theophylline, aminophylline, zafirlukast, betamethasone, dexamethasone, triamcinolone, prednisolone, prednisone or a pharmaceutically acceptable salt, solvate, polymorph, ester thereof, and combinations thereof.

[059] In other embodiments, the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material may be ibuprofen. [060] In yet other embodiments, the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material may be paracetamol, hyrocodone, oxycodone, the triptans including eletriptan, rizatriptan, zolmitriptan; the benzodiazepines including diazepam, flurazepam, flunitrazepam, temazepam, alprazolam, lorazepam, fexofenadine, metoclopramide, loperamide, zolpidem, zopiclone, loratadine, ondansetron, granisetron, tadalafil, vardenafil, sildenafil, ranitidine, famotidine, codeine, fentanyl, tramadol, pseudoephedrine, phenylpropanolamine, dextromethorphan, chlorpheniramine, diphenhydramine, cetirizine, cimetidine, pharmaceutically acceptable salts thereof, or combinations thereof.

[061] In yet other embodiments, the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material may be paracetamol.

[062] In embodiments of the present disclosure, the at least one non-swelling pH dependent enteric release retardant may be selected from a group including polymethacrylic acid derivatives, cellulose derivatives, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate, cellulose benzoate phthalate, cellulose propionate phthalate, or combinations thereof.

[063] In some embodiments, the at least one non-swelling pH dependent enteric release retardant may be selected from a group including acrylic copolymer based pH dependent release retardant include acrylic acid copolymer, methyl acrylate acrylic acid copolymer, methyl acrylate methacrylic acid copolymer, butyl acrylate acrylic acid copolymer, methacrylic acid methyl methacrylate copolymer, methacrylic acid ethyl acrylate copolymer, methyl acrylate methacrylic acid octyl acrylate copolymer, or combinations thereof.

[064] In some embodiments, the at least one non-swelling pH dependent enteric release retardant may include methacrylic acid methyl methacrylate copolymer, such as Eudragit®L100, and Eudragit®S100, methacrylic acid ethyl acrylate copolymer, such as Eudragit®L100-55, or combinations thereof. [065] In some embodiments, the pharmaceutical composition may include methacrylic acid methyl methacrylate copolymer and methacrylic acid ethyl acrylate copolymer at a ratio of 5: 1 by weight.

[066] In other embodiments, the pharmaceutical composition may include methacrylic acid methyl methacrylate copolymer and methacrylic acid ethyl acrylate copolymer at a ratio of 3: 1 by weight.

[067] In yet other embodiments, the pharmaceutical composition may include methacrylic acid methyl methacrylate copolymer and methacrylic acid ethyl acrylate copolymer at a ratio of 1 : 1 by weight.

[068] In embodiments of the present disclosure, the at least one non-swelling pH dependent nonenteric release retardant may be selected from a group including polymer based on dimethylaminoethyl methacrylate, neutral methacrylic acid esters, such as Eudragit®E or combinations thereof.

[069] In embodiments of the present disclosure, the at least on pH dependent release retardant hydrogel may include alginic acid, or a pharmaceutically acceptable salt thereof.

[070] In some embodiments, the at least on pH dependent release retardant hydrogel may be sodium alginate.

[071] In some embodiments, the pharmaceutical composition may include from about 5% to about 90% by weight of the least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material.

[072] In other embodiments, the pharmaceutical composition may include from about 1% to about 35% by weight of the at least one non-swelling pH dependent enteric polymer.

[073] In yet other embodiments, the pharmaceutical composition may include from about 5% to about 25% by weight of the at least one non-swelling pH dependent enteric polymer.

[074] In some embodiments, the pharmaceutical composition may include from about 1% to about 35% by weight of the at least one non-swelling pH dependent non-enteric polymer. [075] In other embodiments, the pharmaceutical composition may include from about 5% to about 25% by weight of the at least one non-swelling pH dependent non-enteric polymer.

[076] In yet other embodiments, the pharmaceutical composition may include from about 5% to about 50% by weight of the at least one pH dependent release retardant hydrogel.

[077] In some embodiments, the pharmaceutical composition may include from about 10% to about 25% by weight of the at least one pH dependent release retardant hydrogel.

[078] In some embodiments, the pharmaceutical composition may include the at least one pH dependent release retardant hydrogel, the at least one at least one non-swelling pH dependent enteric release retardant and the at least one non-swelling pH dependent non-enteric release retardant at a ratio of 3: 1 by weight.

[079] In other embodiments, the pharmaceutical composition may include the at least one pH dependent release retardant hydrogel, the at least one at least one non-swelling pH dependent enteric release retardant and the at least one non-swelling pH dependent non-enteric release retardant at a ratio of 2: 1 by weight.

[080] In yet other embodiments, the pharmaceutical composition may include the at least one pH dependent release retardant hydrogel, the at least one at least one non-swelling pH dependent enteric release retardant and the at least one non-swelling pH dependent non-enteric release retardant at a ratio of 1 : 1 by weight.

[081] In embodiments of the present disclosure, the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material may have a size ranging from about 1 micron to about 800 microns, preferably from about 50 microns to about 500 microns, and more preferably from about 50 microns to about 250 microns.

[082] In embodiments of the present disclosure, the at least one non-swelling pH dependent enteric release retardant may have a size ranging from about 1 micron to about 800 microns, preferably from about 50 microns to about 500 microns, and more preferably from about 50 microns to about 150 microns. [083] In embodiments of the present disclosure, the at least one non-swelling pH dependent nonenteric release retardant may have a size ranging from about 1 micron to about 800 microns, preferably from about 50 microns to about 500 microns, and more preferably from about 50 microns to about 150 microns.

[084] In embodiments of the present disclosure, the at least one pH dependent release retardant hydrogel may have a size ranging from about 1 micron to about 800 microns, preferably from about 50 microns to about 500 microns, and more preferably from about 50 microns to about 150 microns.

[085] Embodiments of the present disclosure further provide a solid oral dosage form including the pharmaceutical composition as described herein, wherein the solid oral dosage form may be a matrix tablet for sustained or controlled release.

[086] In some embodiments, the matrix tablet may be prepared by direct compression, dry granulation, or molding.

[087] In some embodiments, the dosage form may release about 50% by weight or more of an at least weakly acidic, base salt, or neutral pharmaceutically active material within 12 hours from administration.

[088] In other embodiments, the dosage form may release about 80% by weight or more of an at least weakly acidic, base salt, or neutral pharmaceutically active material within 24 hours from administration.

[089] The disclosure is now further illustrated on the basis of Examples and a detailed description from which further features and advantages may be taken. It is to be noted that the following explanations are presented for the purpose of illustration and description only; they are not intended to be exhaustive or to limit the disclosure to the precise form disclosed.

Example 1

Preparation of a solid oral dosage form using Paracetamol as a model pharmaceutical active material [090] For the preparation of paracetamol plain tablets, i.e. without the polymers used in the composition and dosage form of the present disclosure, paracetamol powder was blended with Methocel E5 for about four minutes, then Magnesium Stearate and Talc were added and blended with the powders for about one minute. The resulting mixture was then compressed into tablets using flat-faced punches and die (hydraulic single press, Carver®, U.S.A.) at compaction forces of about 5000 kg for about 30 seconds to yield a compact of sufficient strength. Methocel E5 was added to yield compacts with suitable crushing strengths.

[091] For the preparation of the oral dosage form using the pharmaceutical composition of the present disclosure, tablets containing sodium alginate powder combined with Eudragits® polymers in their base forms (EE and EL grades) or in their salt forms (EE granules and EL granules) were prepared by direct compression. Methocel E5 was blended with lactose and the ternary polymeric combination for about four minutes, then Magnesium Stearate and Talc were added and blended with the resulting mixture for about one minute. The final mixture was then compressed into tablets using flat-faced punches and die (hydraulic single press, Carver®, U.S.A) at compaction forces of about 5000 kg for about 30 seconds.

[092] In a first preparation, the average tablet weight was 1300 mg, and contained the following percentages of materials by weight:

Paracetamol about 76.93%;

Sodium Alginate about 7.27%;

Eudragit EE about 4.85%;

Eudragit EL about 2.42%;

Methocel E5 about 1.46%;

Lactose about 6.71%;

Magnesium Stearate about 0.153%; and Talc about 0.153%.

[093] In a second preparation, the average tablet weight was 1300 mg, and contained the following percentages of materials by weight:

Paracetamol about 76.93%; Sodium Alginate about 9.70%;

Eudragit EE about 4.85%;

Eudragit EL about 4.85%

Methocel E5 about 1.46%;

Lactose about 1.85%;

Magnesium Stearate about 0.153%; and

Talc about 0.153%.

[094] In a third preparation, the average tablet weight was 1300 mg, and contained the following percentages of materials by weight:

Paracetamol about 76.93%;

Sodium Alginate about 4.84%;

Eudragit EE about 2.42%;

Eudragit EL about 2.42%;

Methocel E5 about 1.46%;

Lactose about 11.57%;

Magnesium Stearate about 0.153%; and

Talc about 0.153%.

Example 2

Preparation of a solid oral dosage form using Ibuprofen as a model pharmaceutical active material

[095] For the preparation of ibuprofen plain tablets, i.e. without the polymers used in the composition and dosage form of the present disclosure, ibuprofen powder was blended with Methocel E5 for about four minutes, then magnesium stearate and talc were added and blended with the powders for about one minute. The resulting mixture was then compressed into tablets using flat-faced punches and die (hydraulic single press, Carver®, U.S.A.) at compaction forces of about 5000 kg for about 30 seconds to yield a compact of sufficient strength. Methocel E5 was added to yield compacts with suitable crushing strengths. [096] For the preparation of the oral dosage form using the pharmaceutical composition of the present disclosure, tablets containing sodium alginate powder combined with Eudragits® polymers in their base forms (EE and EL grades) or in their salt forms (EE granules and EL granules) were prepared by direct compression. Methocel E5 was blended with lactose and the ternary polymeric combination for about four minutes, then magnesium stearate and talc were added and blended with the resulting mixture for about one minute. The final mixture was then compressed into tablets using flat-faced punches and die (hydraulic single press, Carver®, U.S.A) at compaction forces of about 5000 kg for about 30 seconds.

[097] In a fourth preparation, the average tablet weight was 1300 mg, and contained the following percentages of materials by weight:

Inbuprofen about 76.19%;

Sodium alginate about 6.71%;

Eudragit EE about 4.47%;

Eudragit EL about 2.19%;

Methocel E5 about 1.81%;

Lactose about 8.24%;

Magnesium Stearate about 0.19%; and Talc about 0.19%.

[098] In a fifth preparation, the average tablet weight was 1300 mg, and contained the following percentages of materials by weight:

Ibuprofen about 76.19%;

Sodium Alginate about 8.94%;

Eudragit EE about 4.45%;

Eudragit EL about 4.49%;

Methocel E5 about 2.2%;

Lactose about 3.35%;

Magnesium Stearate about 0.19 %; and

Talc about 0.19 %. [099] In a sixth preparation, the average tablet weight was 1300 mg, and contained the following percentages of materials by weight:

Ibuprofen about 76.19%;

Sodium Alginate about 4.9%;

Eudragit EE about 2.45%;

Eudragit EL about 2.45%;

Methocel E5 about 2.2 %;

Lactose about 11.43%;

Magnesium Stearate about 0.19 %; and Talc about 0.19 %.

Example 3

Dissolution profile of the solid oral dosage form using Paracetamol as a model pharmaceutical active material

[0100] In this example, reference will be made to FIG. 1, which illustrates a line chart of the dissolution profdes of the three preparations that were prepared in Example 1 above. As depicted from FIG. 1, the three preparations provided between about 70% and 80% release of the paracetamol contained in the tablets in about 24 hours. All dissolution tests were conducted using USP XX II rotating paddle apparatus at rotation speed of 50 rpm using about 900 ml of phosphate buffered medium (pH 6.8 ±0.2), and the temperature was set at about 37 °C. Five milliliter samples were withdrawn at predetermined intervals then filtered through 0.45 pm Millipore filter, the first few drops (about 1-2 ml) were discarded, and the concentration of the drug was measured spectrophotometrically at about 320 nm. Samples taken were replaced by the same volume with fresh medium. The cumulative percentage of drug released was calculated and the average values were plotted against time to obtain the release profiles of the different tablet formulations.

[0101] To investigate the differences between dissolution profiles, data were compared using the modified difference factor formula. The modified difference factor,//' measures the percent error between two curves over time points. The percent error is zero when the test and drug reference profiles are identical and increase proportionally with the dissimilarity between the two dissolution profiles. In order to consider two dissolution profiles similar,// ' value should be close to zero, or it should be less than 15. The difference factor between chosen formulations has been calculated using the following formula: 100

Where n is the sampling number, R and T are the percent dissolution dissolved of the reference and test products at each time point j.

[0102] This may have happened since sodium alginate provided excellent binding and along with other components and can provide adequate controlled release characteristics. In the buffered media (pH 6.8±0.2), Eudragit® starts to dissolve leaving pores and channels for drug leaching out of the matrix. The remaining or the protected (any undissolved) Eudragit® EE is believed to precipitate as insoluble matrix; therefore, along with unfolded and highly gelled sodium alginates will retard the drug release through pores and channeled created upon Eudragit® EL dissolution.

Example 4

Dissolution profile of the solid oral dosage form using Ibuprofen as a model pharmaceutical active material

[0103] In this example, reference will be made to FIG. 2, which illustrates a line chart of the dissolution profdes of the three preparations that were prepared in Example 2 above. As depicted from FIG. 2, the three preparations provided more than 80% release of the ibuprofen contained in the tablets in about 24 hours. All dissolution tests were conducted using USP XX n rotating paddle apparatus at rotation speed of about 50 rpm using about 900 ml of phosphate buffered medium (pH 6.8 ±0.2), and the temperature was set at about 37 °C. About five milliliter samples were withdrawn at predetermined intervals then filtered through 0.45 pm Millipore filter, the first few drops (about 1-2 ml) were discarded, and the concentration of the drug was measured spectrophotometrically at about 320 nm. Samples taken were replaced by the same volume with fresh medium. The cumulative percentage of drug released was calculated and the average values were plotted against time to obtain the release profiles of the different tablet formulations.

[0104] To investigate the differences between dissolution profiles, data were compared using the modified difference factor formula. The modified difference factor,//' measures the percent error between two curves over time points. The percent error is zero when the test and drug reference profiles are identical and increase proportionally with the dissimilarity between the two dissolution profiles. In order to consider two dissolution profiles similar,//' value should be close to zero, or it should be less than 15.

The difference factor between chosen formulations has been calculated using equation 1 :

[0105] This may have happened since sodium alginate provided excellent binding and along with other components and can provide adequate controlled release characteristics. In the buffered media (pH 6.8±0.2), Eudragit® starts to dissolve leaving pores and channels for drug leaching out of the matrix. The remaining or the protected (any undissolved) Eudragit® EE is believed to precipitate as insoluble matrix; therefore, along with unfolded and highly gelled sodium alginates will retard the drug release through pores and channeled created upon Eudragit® EL dissolution.

Example 5

Comparison of Dissolution profiles of the solid oral dosage form using Ibuprofen as a model pharmaceutical active material in preparations of the present disclosure and Ibuprofen drug available in the Jordanian market

[0106] In this example, reference will be made to FIG. 3, which illustrates a line chart of the dissolution profiles of two preparations that were prepared in Example 2 above, and Ibuprofen Retard that is available in the Jordanian market. As depicted from FIG. 3, the two preparations and Ibuprofen Retard provided more than 80% release of the ibuprofen contained in the tablets in about 24 hours.

[0107] Originator tablets were treated in a similar way to the pharmaceutical composition of the present disclosure in terms of dissolution. Dissolution tests were conducted using USP XX II rotating paddle apparatus at rotation speed of about 50 rpm using about 900 ml of phosphate buffered medium (pH 6.8 ±0.2), and the temperature was set at about 37 °C. About five milliliter samples were withdrawn at predetermined intervals then filtered through 0.45 pm Millipore filter, the first few drops (about 1-2 ml) were discarded, and the concentration of the drug was measured spectrophotometrically at about 320 nm. Samples taken were replaced by the same volume with fresh medium. The cumulative percentage of drug released was calculated and the average values were plotted against time to obtain the release profiles of the different tablet formulations.

[0108] While embodiments of the present disclosure have been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various additions, omissions, and modifications can be made without departing from the spirit and scope thereof.

[0109] In describing and claiming the present invention, the following terminology was used. [0110] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.

[0111] As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a defacto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.

[0112] Concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub -ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a numerical range of approximately 1 to approximately 4.5 should be interpreted to include not only the explicitly recited limits of 1 to approximately 4.5, but also to include individual numerals such as 2, 3, 4, and sub-ranges such as 1 to 3, 2 to 4, etc. The same principle applies to ranges reciting only one numerical value, such as “less than approximately 4.5,” which should be interpreted to include all of the above-recited values and ranges. Further, such an interpretation should apply regardless of the breadth of the range or the characteristic being described.

[0113] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the presently disclosed subject matter belongs. Although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the presently disclosed subject matter, representative methods, devices, and materials are now described.

[0114] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about”. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter.

[0115] As used herein, the term “about”, when referring to a value or to an amount of mass, weight, time, volume, concentration or percentage is meant to encompass variations of in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed method.

Claims

CLAIMS What is claimed is:

1. A pharmaceutical composition comprising at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material, at least one non-swelling pH dependent enteric release retardant, at least one non-swelling pH dependent non-enteric release retardant, and at least one pH dependent release retardant hydrogel, and a pharmaceutically acceptable carrier/excipient.

2. The pharmaceutical composition of claim 1 , wherein the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material belongs to the group comprising analgesics, antipyretics, anti-inflammatory agents, antidepressants, anti-asthma agents, antibiotics, antivirals, antifungals, anticonvulsants, antidiabetics, anti-gout agents, antihistamines and anti-allergy agents, antihypertensives, anti-migraine agents, anti- muscarinics, antinauseants, antineoplastics, antipsoriatics, antispasmodics and motility agents, antithrombotics, bone modulating agents, bronchodilators, cardiovascular drugs, diuretics, diagnostic agents, dopaminergics, anxiolytics, sedatives, hypnotics and antipsychotics, immunomodulators, lipid regulating agents, muscle relaxants, nutritional supplements, sedatives, thyroid agents, uricosurics, vasodilators, vitamins, or combinations thereof.

3. The pharmaceutical composition of claim 2, wherein the weakly acidic, salt of a weak base, or neutral pharmaceutically active material comprises acetyl salicylic acid, diclofenac, fenoprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, naproxen, piroxicam, sulindac, rofecoxib, penicillins, cephalosporins, quinolones, tetracyclines and sulphonamides, trimethoprim, temazepam and flunitrazepam, barbiturates, pamidronic acid, risedronic acid and zoledronic acid, atorvastin, simvastatin, cerivastin, fluvastin, pravastatin, clofibrate, bezafibrate, gemfibrozil, ascorbic acid, captopril, chlorambucil, cyclophosphamide, fluoxetine, norfluoxetine, folic acid, furosemide, fusidic acid, glibenclamide, gliclazide, glutethimide, isoniazid, levodopa, methotrexate, methyldopa, montelukast, nalidixic acid, phenacetin, phenindione, probenecid, rifampicin, sulphasalazine, sulphinpyrazone, thyroxine, tolazamide,

23 tolbutamide, valproic acid, warfarin, sodium cromoglycate, fenoterol, salbutamol, theophylline, aminophylline, zafirlukast, betamethasone, dexamethasone, triamcinolone, prednisolone, prednisone or a pharmaceutically acceptable salt, solvate, polymorph, ester thereof, and combinations thereof. The pharmaceutical composition of claim 2, wherein the weakly acidic, salt of a weak base, or neutral pharmaceutically active material comprises paracetamol, hyrocodone, oxycodone, the triptans including eletriptan, rizatriptan, zolmitriptan; the benzodiazepines including diazepam, flurazepam, flunitrazepam, temazepam, alprazolam, lorazepam; fexofenadine; metoclopramide, loperamide, zolpidem, zopiclone, loratadine, ondansetron, granisetron, tadalafil, vardenafil, sildenafil, ranitidine, famotidine, codeine, fentanyl, tramadol, pseudoephedrine, phenylpropanolamine, dextromethorphan, chlorpheniramine, diphenhydramine, cetirizine, cimetidine, pharmaceutically acceptable salts thereof, or combinations thereof. The pharmaceutical composition of claim 1, wherein the at least one non-swelling pH dependent enteric release retardant is selected from a group comprising polymethacrylic acid derivatives, cellulose derivatives, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimelliate, cellulose benzoate phthalate, cellulose propionate phthalate, or combinations thereof. The pharmaceutical composition of claim 1, wherein the at least one non-swelling pH dependent enteric release retardant is selected from a group comprising acrylic copolymer based pH dependent release retardant include acrylic acid copolymer, methyl acrylate acrylic acid copolymer, methyl acrylate methacrylic acid copolymer, butyl acrylate acrylic acid copolymer, methacrylic acid methyl methacrylate copolymer, methacrylic acid ethyl acrylate copolymer, methyl acrylate methacrylic acid octyl acrylate copolymer, or combinations thereof. The pharmaceutical composition of claim 1, wherein the at least one non-swelling pH dependent enteric release retardant comprises methacrylic acid methyl methacrylate copolymer, methacrylic acid ethyl acrylate copolymer, or combinations thereof. The pharmaceutical composition of claim 7, wherein the composition comprises methacrylic acid methyl methacrylate copolymer and methacrylic acid ethyl acrylate copolymer at a ratio of 5: 1 by weight. The pharmaceutical composition of claim 7, wherein the composition comprises methacrylic acid methyl methacrylate copolymer and methacrylic acid ethyl acrylate copolymer at a ratio of 3: 1 by weight. The pharmaceutical composition of claim 7, wherein the composition comprises methacrylic acid methyl methacrylate copolymer and methacrylic acid ethyl acrylate copolymer at a ratio of 1 : 1 by weight. The pharmaceutical composition of claim 1, wherein the at least one non-swelling pH dependent non-enteric release retardant is selected from a group comprising polymer based on dimethylaminoethyl methacrylate, neutral methacrylic acid esters, or combinations thereof. The pharmaceutical composition of claim 1, wherein the at least on pH dependent release retardant hydrogel comprises alginic acid, or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 12, wherein the at least on pH dependent release retardant hydrogel comprises sodium alginate. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises from about 5% to about 90% by weight of the least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises from about 1% to about 35% by weight of the at least one non-swelling pH dependent enteric polymer. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition comprises from about 5% to about 25% by weight of the at least one non-swelling pH dependent enteric polymer. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises from about 1% to about 35% by weight of the at least one non-swelling pH dependent non-enteric polymer. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition comprises from about 5% to about 25% by weight of the at least one non-swelling pH dependent non-enteric polymer. The pharmaceutical composition of claim 17, wherein the pharmaceutical composition comprises from about 5% to about 50% by weight of the at least one pH dependent release retardant hydrogel. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition comprises from about 10% to about 25% by weight of the at least one pH dependent release retardant hydrogel. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises the at least one pH dependent release retardant hydrogel, the at least one at least one non-swelling pH dependent enteric release retardant and the at least one non-swelling pH dependent non-enteric release retardant at a ratio of 3 : 1 by weight. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises the at least one pH dependent release retardant hydrogel, the at least one at least one non-swelling pH dependent enteric release retardant and the at least one non-swelling pH dependent non-enteric release retardant at a ratio of 2: 1 by weight. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises the at least one pH dependent release retardant hydrogel, the at least one at least one non-swelling pH dependent enteric release retardant and the at least one non-swelling pH dependent non-enteric release retardant at a ratio of 1 : 1 by weight. The pharmaceutical composition of claim 1 , wherein the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material has a size ranging from about 1 micron to about 800 microns.

26 The pharmaceutical composition of claim 24, wherein the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material has a size ranging from about 50 microns to about 500 microns. The pharmaceutical composition of claim25, wherein the at least one weakly acidic, salt of a weak base, or neutral pharmaceutically active material has a size ranging from about 50 microns to about 250 microns. The pharmaceutical composition of claim 1, wherein the at least one non-swelling pH dependent enteric release retardant has a size ranging from about 1 micron to about 800 microns. The pharmaceutical composition of claim 27, wherein the at least one non-swelling pH dependent enteric release retardant has a size ranging from about 50 microns to about 500 microns. The pharmaceutical composition of claim 28, wherein the at least one non-swelling pH dependent enteric release retardant has a size ranging from about 50 microns to about 150 microns. The pharmaceutical composition of claim 1, wherein the at least one non-swelling pH dependent non-enteric release retardant has a size ranging from about 1 micron to about 800 microns. The pharmaceutical composition of claim 30, wherein the at least one non-swelling pH dependent non-enteric release retardant has a size ranging from about 50 microns to about 500 microns. The pharmaceutical composition of claim 31, wherein the at least one non-swelling pH dependent non-enteric release retardant has a size ranging from about 50 microns to about 150 microns. The pharmaceutical composition of claim 1, wherein the at least one pH dependent release retardant hydrogel has a size ranging from about 1 micron to about 800 microns.

27 The pharmaceutical composition of claim 33, wherein the at least one pH dependent release retardant hydrogel has a size ranging from about 50 microns to about 500 microns. The pharmaceutical composition of claim 34, wherein the at least one pH dependent release retardant hydrogel has a size ranging from about 50 micron to about 150 microns. A solid oral dosage form comprising the pharmaceutical composition according to any of the preceding claims, wherein the solid oral dosage form is a matrix tablet for sustained or controlled release. The solid oral dosage form of claim 36, wherein the matrix tablet is prepared by direct compression, dry granulation, or molding. The solid oral dosage form of claim 36, wherein such dosage form releases about 50% by weight or more of an at least weakly acidic, base salt, or neutral pharmaceutically active material within 12 hours from administration. The solid oral dosage form of claim 36, wherein such dosage form releases about 80% by weight or more of an at least weakly acidic, base salt, or neutral pharmaceutically active material within 24 hours from administration.

28