Controlled-release formulations containing dorotaberine or its salts

Abstract

Providing a controlled-release formulation containing dorotaberine or its salts, or an active substance with a similar tendency to degrade through oxidation / hydrolysis. [Solution] The present invention provides a controlled-release formulation containing dorotaberine or a salt thereof, or an active substance with a similar tendency to degrade through oxidation / hydrolysis. The present invention provides a once- or twice-daily controlled-release formulation of dorotaberine or a salt thereof that avoids fluctuations in plasma levels, reduces pill burden and side effects through a simplified dosing schedule, and consequently improves patient compliance. The present invention also provides a method for preparing a controlled-release formulation of dorotaberine or a salt thereof. The present invention further provides a controlled-release formulation of dorotaberine or a salt thereof for the treatment of at least one symptom of gastrointestinal, biliary, urinary, and gynecological disorders characterized by a spastic state of smooth muscle in a subject.

Description

Technical Field

[0001] Related Applications This application claims priority to Indian Patent Application No. 202011010072, filed on March 9, 2020, the invention of which is incorporated herein by reference in its entirety.

[0002] Field of the Invention In some aspects, the present invention relates to a controlled release formulation comprising drotaverine or a salt thereof or a similar active substance, which tends to decompose by oxidation and hydrolysis, and a method for preparing the same. In some aspects, the present invention relates to the treatment of symptoms of gastrointestinal, biliary, urinary and / or gynecological disorders characterized by smooth muscle spasm by administering the controlled release formulation of the present invention.

Background Art

[0003] Background of the Invention Preparing formulations that provide controlled release of pharmacologically active substances upon oral administration to humans and animals is well known in the art. Controlled release (CR) formulations reduce the dosing frequency required to maintain a therapeutically effective plasma drug concentration. In addition, by providing a more constant blood concentration, such formulations reduce the large variations in observed plasma levels between doses. Controlled release formulations are intended to provide a pharmacological action for a longer period after administration compared to that typically achieved after administration of an immediate release (IR) dosage form. Such a longer period of response provides a therapeutic effect not achieved with immediate release preparations. Further, controlled release formulations result in better patient compliance.

[0004] Drotaverine HCl [(Z)-1-(3,4-diethoxybenzylidene)-6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline] is a benzylisoquinoline derivative and is an analogue of papaverine.

[0005]

Chemical Formula

[0006] The molecular weight of dorotaverine is 397.50 g / mol, and the empirical formula is C 24 H 31 It is NO4. Dorotaverine is a potent antispasmodic that acts directly on smooth muscle by inhibiting phosphodiesterase activity, and it has no side effects due to anticholinergic effects. Because dorotaverine is a selective inhibitor of phosphodiesterase isozyme IV, it has been found to be useful in controlling spastic disorders of smooth muscle. Dorotaverine has a two-step mechanism of action. First, it inhibits the enzyme phosphodiesterase IV (PDE IV). This causes an increase in cyclic adenosine monophosphate (cAMP) levels in smooth muscle, and then free calcium ions (Ca 2+ This leads to a decrease in calcium concentration. Secondly, it inhibits calmodulin (CM), a calcium-binding protein. The inhibition of calmodulin is linked to Ca 2+ The decrease in ions is due to the "calmodulin-calcium complex" (CM-Ca 2+ This leads to inhibition of formation. This process inhibits myosin light chain kinase enzyme (MLCK), leading to dephosphorylation of the actomyosin phosphate complex, which in turn causes the normalization of smooth muscle.

[0007] Dorotaverine is a very potent and safe anticonvulsant (antispasmodic) agent suitable for oral and parenteral administration. Dorotaverine is currently marketed as a conventional IR product indicated for smooth muscle spasms. It reduces and prevents smooth muscle spasms in various organs, regardless of their function and nerve distribution. Primarily, the drug is indicated, both alone and in combination, for the treatment of various gastrointestinal, biliary, urinary, and / or gynecological disorders characterized by smooth muscle spasticity.

[0008] For example, Dorotaberine is indicated for the following: i) Spasmodic conditions of the gastrointestinal tract: Irritable bowel syndrome, biliary colic, and spasmodic conditions of the biliary tract, such as gallstones, cholecystitis, and cholangitis. ii) Renal colic and spasmodic conditions of the urogenital tract: kidney stones, ureteral stones, pyelonephritis, cystitis. iii) Spasmodic state of the uterus: dysmenorrhea, threatened miscarriage, convulsive labor.

[0009] It is also widely used in the treatment of spastic pain due to gastric and duodenal ulcers, and in enhancing labor before beneficial diagnostic methods are employed. The approved daily doses are 120-240 mg for adults (in 2-3 divided doses), 40-120 mg for children 1-6 years (in 2-3 divided doses), and 80-200 mg for children over 6 years (in 2-5 divided doses). Due to its non-anticholinergic nature, drotaverine can be safely prescribed over long periods. Drotaverine is registered in over 50 countries in Europe, Asia, Africa, and Central America.

[0010] In indications such as irritable bowel syndrome (IBS), where pain is the primary symptom, antispasmodics remain the mainstay of treatment. Dorotaverine exhibits a normalizing effect on intestinal smooth muscle, which helps relieve pain but does not have the side effects of anticholinergic drugs. Anticholinergic antispasmodics are avoided in IBS where constipation is present (IBS - constipation is the primary symptom).

[0011] Drotabrine, through its unique site-selective action, reduces IBS spasms and normalizes smooth muscle contraction. Therefore, it does not cause constipation, making it suitable for use in all types of IBS (diarrhea-dominant IBS, constipation-dominant IBS, and mixed IBS). The anticonvulsant drotabrine has long been used to relieve pain in irritable bowel syndrome (IBS). However, the problem of having to administer the drug two to three times a day remains, which can lead to poor patient compliance and inconvenience.

[0012] Abdominal pain is a common problem in children. Various disorders can cause acute abdominal pain in children. Dorotaberine is an effective and safe medication for managing recurrent abdominal pain in infants. It is the most commonly used off-label drug therapy for gastrointestinal problems in preschool and school-aged children.

[0013] Dorotaverine was associated with an improved first stage of labor course in nulliparous women without exacerbating fetal-maternal crisis. Dorotaverine is considered an effective and safe medication for shortening the duration of the first stage of spontaneous labor in nulliparous women.

[0014] Dorotaberine is effective and beneficial in improving and / or treating benign prostatic hyperplasia, urinary tract disorders, disorders associated with bladder dysfunction, lower urinary tract symptoms with or without benign prostatic hyperplasia, urinary incontinence, bladder voiding dysfunction with or without benign prostatic hyperplasia, interstitial cystitis, and overactive bladder.

[0015] Dorotaberine, used alone or in combination, is highly effective in relieving painful spasms in a variety of diseases originating in gastroenterology, urology, gynecology, and / or obstetrics, and is a first-line drug in emergency medicine. Dorotaberine does not mask the symptoms of "acute abdominal pain," and this characteristic of dorotaberine makes it unique.

[0016] Antispasmodic dorotaberine and antiprostaglandin-like mefenamic acid can be used as analgesia for women undergoing IUD (intrauterine device) insertion in an outpatient setting. Dorotaberine relieves early-onset pain and enhances the sustained analgesic effect of mefenamic acid. The combination of dorotaberine and mefenamic acid is effective in reducing pain during the procedure, and its effect lasts longer than that of paracervical block or intravenous sedation.

[0017] The addition of dorotaberine to aceclofenac provides a significant therapeutic effect in relieving pain associated with primary dysmenorrhea. Dorotaberine produces rapid analgesia through its antispasmodic effect, while aceclofenac provides sustained analgesia. Therefore, the fixed-dose immediate-release (IR) combination of aceclofenac and dorotaberine should be considered an effective and well-accepted treatment for primary dysmenorrhea.

[0018] Compared to subjects treated with PCM alone, subjects with acute infectious gastroenteritis showed a significant reduction in abdominal pain when treated with drotaverine hydrochloride (80 mg) and PCM (500 mg), demonstrating the efficacy of the fixed-dose IR combination of drotaverine hydrochloride (80 mg) and Paracetamol (PCM) 500 mg in improving abdominal pain associated with acute infectious gastroenteritis.

[0019] Other possible combinations with dorotaberine have been tested in the literature: WO2016075617 discloses that a combination of analgesics and anticonvulsants, such as ibuprofen (400 mg) and dorotaberine (80 mg), for the treatment of menstrual pain and abdominal cramps relieves menstrual-related pain and reduces abdominal cramps.

[0020] Zhu, J. et al (2017) disclose that combination therapy with ketorolac, diclofenac, and dorotaverine is effective in reducing acute renal colic, particularly pain, due to intermediate and proximal ureteral stones, and that this treatment was associated with a reduction in the use of emergency analgesia. All of these commercially available combinations with dorotaverine are available as immediate-release formulations, and these combinations do not disclose controlled-release formulations.

[0021] Pharmacokinetic parameters of dorotaverine, such as elimination, half-life, plasma clearance, renal clearance, and apparent volume of distribution, are not affected by the route of drug administration (Bolaji OO et al., 1996). The pharmacokinetic parameters of immediate-release (IR) dorotaverine tablets 80 mg were tested. The drug is primarily eliminated via non-renal routes, as renal clearance accounts for only 0.31 ± 0.13% of total plasma clearance. Absolute bioavailability is variable and subject-dependent, ranging from 24.5 to 91%, with a mean of 58.2 ± 18.2% (mean ± SD). The high degree of variability in the bioavailability of dorotaverine HCl after oral administration suggests that significant individual differences in therapeutic response to the drug may be attributable to these differences. Pharmacokinetic and bioavailability studies showed that dorotaverine exhibited rapid absorption, with onset of action within 12 minutes of oral administration of an 80 mg IR tablet and nearly 90% drug absorption from the small intestine. Peak plasma levels were achieved 1–3 hours later, while the elimination half-life ranged from 7–11.95 hours. Dorotaverine was considered very safe in toxicological studies because its reported oral LD50 is >1000 mg / kg body weight, and therefore it has a broad therapeutic factor (Blasko G, 1996).

[0022] CN102149382 provides that dorotaberine, in free or salt form, is helpful in improving and / or treating benign prostatic hyperplasia, urinary tract disorders, conditions associated with bladder dysfunction, lower urinary tract symptoms associated with or unrelated to benign prostatic hyperplasia, urinary incontinence, bladder dysfunction, interstitial cystitis, and overactive bladder associated with or unrelated to benign prostatic hyperplasia; here, the preferred dorotaberine salt is dorotaberine HCl. The provided pharmaceutical compositions are suitable for administration by oral or parenteral routes and may be further prepared for sublingual, subcutaneous, intramuscular, intravenous, intradermal, topical or rectal administration. The pharmaceutical compositions are prepared by incorporating (one or more) pharmaceutical additives in a ratio ranging from 1% to 90% by weight, based on the weight of dorotaberine or its salt. Examples of excipients used in the preparation of solid pharmaceutical compositions include lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, and calcium carbonate.

[0023] When preparing a solid composition in tablet form, the active ingredient is mixed with excipients. The tablets can be coated with sucrose or other suitable materials, or they can be treated so that they have extended or delayed activity, and they continuously release a predetermined amount of the active ingredient. Preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules. In the preparation of a liquid composition for oral administration, the use of conventional inert diluents such as water or vegetable oils has been reported. The liquid composition is disclosed to incorporate adjuvants such as wetting agents, suspending aids, sweeteners, flavorings, colorants, preservatives, etc. in addition to the inert diluent. The resulting liquid composition can be filled into capsules made of an easily absorbable material such as gelatin. The invention of CN102149382 provides examples of solvents or suspension media used in the preparation of compositions for parenteral administration, namely, injections and suppositories including water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin, etc. Examples of base materials used for suppositories include, for example, cocoa butter, emulsified cocoa butter, lauryl lipids, witepsol. When the composition of CN102149382 is administered to humans by the parenteral or oral route, the daily dose of drotaverine varies between 15 and 250 mg; preferably between 120 and 240 mg. More preferably, the dose of drotaverine HCl is 40 mg once to six times a day or 80 mg once to three times a day as an immediate release dosage form. The effect of drotaverine was tested in the induction plateau of contractions in isolated human detrusor muscles. CN102149382 has shown that drotaverine causes a significant concentration-dependent relaxation of contractions in human detrusor muscle.

[0024] EP2709599 B1 relates to a stable, immediate-release pharmaceutical composition of dorotaberin HCl for oral administration. The document provides a pharmaceutical composition in the form of a soft capsule for oral administration, comprising 5-30% (w / w) dorotaberin HCl; and at least 60% (w / w) a liquid mixture of a nonionic hydrophilic surfactant and a nonionic hydrophobic surfactant (the nonionic hydrophilic surfactant being polysorbate 80 and the nonionic hydrophobic surfactant being propylene glycol monocaprilate; the weight ratio of dorotaberin HCl to the liquid mixture of surfactants being 1:3-1:7). EP2709599 B1 addresses a problem relating to gelatin-based compositions that are thought to be due to crosslinking of gelatin-containing products (with a clear decrease in degradation over time). Crosslinking causes the formation of a swollen, very thin, tough, rubbery, water-insoluble film, also known as a thin film. The thin film acts as a barrier, limiting the release of the drug. Drugs such as dorotaberine or its pharmaceutically acceptable salts or hydrates tend to react with gelatin, thereby inducing crosslinking, which increases the likelihood of degradation during stability testing. EP2709599 B1 provides that such gelatin crosslinking can be overcome by the addition of certain weak acids, such as tartaric acid, citric acid, or a combination thereof, combined with glycine in an amount of about 0.1–1.0% by weight of the gelatin shell formulation. Furthermore, the document provides that preferred gelatin compositions for use in assembling soft gelatin capsules for use with dorotaberine compositions include gelatin, as well as (one or more) plasticizers such as propylene glycol and sorbitol. The results reveal that 100% (w / w) of dorotaberine HCl dissolved in NoSpa® tablets is released after 30 minutes, and after 45 minutes in relation to the composition according to EP2709599 B1.

[0025] EP1200088A2 relates to an analgesic / antipyretic immediate-release composition in tablet form containing paracetamol and drotaverine HCl, which is a mixture of one or more organic acids or potassium sorbate as stabilizers, one or more commonly used pharmaceutical adjuvants, and optionally codeine phosphate as an active ingredient. Commonly used bulking agents and excipients used are lactose, mannitol, sorbitol, glidants such as magnesium stearate, stearic acid and talc, further substances facilitating disintegration such as poly(vinyl-pyrrolidone), starch, cellulose and pigments such as iron(III) oxide or organic dyes. The pharmaceutical composition of EP1200088A2 optionally utilizes a saccharide-type bulking agent and an organic acid as a stabilizer. It has been found that the quantity of decomposition products of the composition of EP1200088A2 is low even after a long time under the conditions of accelerated and long-term stability tests. Tablets manufactured according to EP1200088A2 have been reported to be stable in terms of uniform physical and chemical aspects.

[0026] Indian Patent Application 1625 / DEL / 2006 provides a solid oral immediate-release pharmaceutical composition containing two therapeutic active substances for use as an antispasmodic and analgesic composition. The application provides that antispasmodics such as drotaverine are often formulated with anti-inflammatory drugs whenever there are inflammatory conditions associated with spastic diseases. The application discloses that when two drugs, namely ketorolac tromethamine and drotaverine HCl, are formulated into a dosage form as a mixture, they undergo a certain amount of decomposition. The application avoids incompatibility between drugs by avoiding contact between ketorolac and drotaverine, and formulates a solid oral pharmaceutical composition as a two-layer tablet. The solid dosage form further comprises a pharmaceutically acceptable carrier (including one or more diluents, binders, disintegrants, flow promoters and lubricants).

[0027] RU2535049C1 discloses a process for preparing stable dorotaberine hydrochloride. To protect dorotaberine hydrochloride from oxidative decomposition / decomposition, dorotaberine hydrochloride is crystallized in the presence of a stabilizing additive, a mixture of citrate and its sodium salt, in an amount of up to 1.0 wt% of the dorotaberine hydrochloride supplied for crystallization. The document discloses a method for producing a stable substance of dorotaberine hydrochloride by introducing a stabilizing additive, characterized in that the stabilizing additive is introduced into the reaction mass during the recrystallization process of dorotaberine hydrochloride from solution. RU2199308C1 discloses that the stabilization of dorotaberine hydrochloride is carried out by introducing a stabilizing additive, such as sodium sulfite or ethyl alcohol, into solution.

[0028] WO2019149917A1 discloses an immediate-release pharmaceutical composition comprising metamisole, dorotaverine, and caffeine in a single dosage form, characterized in that the metamisole in the composition exists in the form of metamisole-containing granules, and dorotaverine and caffeine are present on the outside of the granules. WO2019149917A1 provides that the combination of metamisole, dorotaverine, and caffeine is known for its potent analgesic effect, and that such a combination can be used in cases of severe and persistent pain and fever. Furthermore, the combination of an anticonvulsant (dorotaverine) and an analgesic (metamisole) efficiently relieves spastic pain occurring during migraines, menstruation, colic, etc. A third active substance (caffeine) in the composition helps to enable the initial action of the drug and enhances the analgesic effects of the other substances (metamisole and dorotaverine). All of the above cited references disclose immediate-release preparations, and none of them relate to controlled-release formulations of dorotaberine.

[0029] Om Prakash et al., 2013, reported the development of a floating drug delivery system containing dorotaberine. The primary objective of the study reported by Om Prakash was to develop a floating tablet of dorotaberine HCl that extends gastric residence time with a total floating time of more than 24 hours. The study also discloses the use of a combination of hydrophilic (HPMC) and hydrophobic (Carbopol-934P) polymers as essential components, with sodium carbonate and citrate as gas-forming agents, to ensure a 24-hour drug release profile. The formulations from this study exhibit very slow degradation, with approximately 50% drug release within 8 hours; 75% drug release within 16 hours; and approximately 99% degradation within 24 hours. This is merely a research report and appears to have no industrial applicability. The objective of this research report is to extend gastric residence time, and there is no disclosure of a viable controlled-release formulation. Based on this prior art teaching, a person skilled in the art cannot develop a formulation of dorotaberine with a controlled-release profile of 12–24 hours.

[0030] Drotaverin HCl is highly susceptible to oxidation. In neutral or alkaline culture media, it undergoes oxidative degradation by oxidative decomposition to drotaveraldine, and simultaneously, upon exposure to light, the molecule is broken down to perparin, which is then decomposed to perparaldin by dehydrogenation.

[0031] Suitability studies have shown that the chemical stability of solid pharmaceutical compositions of dorotaberine hydrochloride is significantly affected by the moisture content of tablet excipients, granules, and tablets, as well as the chemical reactions of the composition. Available prior art has provided no clues for preparing a chemically stable controlled-release dosage form of dorotaberine.

[0032] The interaction of dorotaberine HCl with many tableting excipients, such as magnesium stearate (which is widely used in tablet formulation), was tested, and it was found that the degradation of dorotaberine HCl is greatly accelerated by its alkaline hydrolysis, especially in the presence of moisture. In addition, the chemical instability of dorotaberine hydrochloride is significantly affected by the pH of the formulation, and the degradation rate was greatly increased in the presence of magnesium stearate. Surprisingly, the developed formulation of this invention demonstrated good stability even in the presence of magnesium stearate, and thus successfully overcame the limitations of magnesium stearate addition reported in the prior art.

[0033] To ensure minimal degradation of dorotaberin HCl in the finished product, it is also necessary to control the moisture content level. Furthermore, similar forms of dorotaberin HCl or other oxygen-sensitive drug molecules may also require encapsulation, special coating, or a microenvironment with an inert gas, such as nitrogen, in the primary-filled finished product to further improve shelf life.

[0034] Probably due to dorotaverine's extremely high susceptibility to oxidation and hydrolysis degradation, and for other reasons, a controlled-release (CR) formulation of dorotaverine was never considered possible or suitable.

[0035] The goal of any drug delivery system is to deliver a therapeutic dose of drug into the body to achieve and then maintain a desired drug concentration. Consistent, sustained delivery of the drug results in better patient compliance, as the patient does not require as many doses. Controlled-release formulations are also safer, as they reduce the side effects associated with dangerous spikes in drug concentration. This creates a need for CR formulations with less frequent dosing, preferably once per day. In particular, there is a need in the art for an oral formulation of dorotaverine that provides controlled release of the drug while ensuring rapid onset of action. The present invention provides a CR formulation of dorotaverine or a salt thereof that releases the drug from a single-dose tablet or capsule to release the drug throughout the course of the day.

[0036] One embodiment of the formulation of the present invention exhibits a "biphasic release profile" having good uptake of the "immediate and sustained" release portion for immediate and sustained analgesia.

[0037] References: 1. Bolaji OO, Onyeji CO, Ogundaini AO, Olugbade TA, Ogunbona FA. Pharmacokinetics and bioavailability of Drotaverine in humans. Eur J Drug Metab Pharmacokinet. 1996; Jul-Sep; 21(3):217-21. 2. Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent: Drotaverine. J Am Med Assoc Ind. Physicians' Update 1998; 1:63-9. 3. Om Prakash, S Saraf, M Rahman, Neeraj Agnihotri, and Vinay Pathak. Formulation and Evaluation of Floating Drotaverine Hydrochloride Tablets Using Factorial Design. Res J Pharm, Bio and Chem Sci, 2003; Oct-Dec; 4(4): 546-555. 4. Zhu, J. & Cao, Y. & Yu, M.-L & Liu, C. & He, W. & Zeng, B. & Li, J. Efficacy and safety of combination therapy with Drotaverine and ketorolac versus ketorolac mono-therapy for acute renal colic: A retrospective study of 322 patients. International Journal of Clinical and Experimental Medicine. 2017; 10; 3454-3461.

[0038] In one embodiment, the present invention provides a controlled-release formulation of dorotaberine or a salt thereof or a similar active substance (which is prone to oxidation and hydrolysis degradation). In another embodiment, the present invention provides a stable formulation of dorotaberine or a salt thereof or a similar active substance (which is prone to oxidation and hydrolysis degradation) for one or two doses per day (over approximately 12 to 24 hours).

[0039] In another embodiment, the present invention provides a stable, controlled-release formulation of dorotaberine or a salt thereof that has more uniform and predictable oral bioavailability compared to prior art formulations. In another embodiment, the present invention provides a method for preparing a release-controlled formulation of dorotaberine or a salt thereof or a similar active substance (which is prone to oxidation and hydrolysis degradation).

[0040] In another embodiment, the present invention provides a treatment for gastrointestinal, biliary, urinary, and / or gynecological symptoms characterized by a spastic state of smooth muscle, by administering a controlled-release formulation of the present invention.

[0041] Therefore, in key embodiments, the present invention provides a stable CR formulation comprising dorotaberine or a salt thereof for once- or twice-daily administration using an acidifying agent and a polymer. The selected polymer has a variety of hydrophilic, hydrophobic, swelling, disintegration, and pH-dependent solubility properties to ensure flexibility in controlling drug release. The developed CR formulation can be administered in the form of multilayer, multi-coated tablets or capsules. In some embodiments, the dorotaberine CR formulations disclosed herein are administered once daily and may lead to better patient convenience and compliance. They may be formulated as single-layer, double-layer, triple-layer tablets or multi-coated mini-tablets or beads or pellets compressed as MUPS (Multiple Unit Pellet System) tablets, or filled into capsules. The capsule shell used may be made of gelatin or a non-gelatin base material.

[0042] To identify various parameters of the tablet formulations, they were subjected to testing of the IR layer and the CR (controlled release) layer. The best basic formulations having both IR and CR layers were selected based on their degradation profiles. Various concentrations of superdisintegrants, namely sodium starch glycolate, croscarmellose sodium, and crospovidone, were used alone or in combination to improve drug release in the IR layer, and various grades of polymers were used alone or in various concentrations to develop the CR layer.

[0043] Oral administration is the simplest and most commonly used route of drug delivery due to its ease of administration, high patient compliance, cost efficiency, minimal infertility risk, and flexibility in dosage form design. Dorotaberine has a rapid onset of action, beginning pain relief within 12 minutes of oral administration. Therefore, the advantage of the composition and method of the present invention is to improve disease management by adjusting the drug release rate profile of dorotaberine drug delivery compared to IR tablets when administered orally. This, in turn, leads to a reduction in the frequency of dosing from three times a day to once or twice a day (providing greater convenience and better patient compliance).

[0044] In another embodiment, the dorotaberine CR formulation of the present invention ensures uniform and therapeutically effective predicted plasma concentration levels in the bloodstream over a 12-24 hour period, thereby avoiding the fluctuations in drug plasma levels typically observed with IR tablet therapy. The once-daily controlled-release formulation also reduces the pill burden on the patient. The CR formulation of dorotaberine or its salts provided by the present invention is designed such that a sufficient amount of drug is rapidly released within the first hour to achieve plasma levels similar to those of an immediate-release formulation, and The remaining drug is gradually released over a 24-hour period, maintaining drug concentrations within the therapeutic range. Thus, the formulation of the present invention ensures both immediate and sustained release of dorotaverine or its salts. Compared to immediate-release formulations, the dorotaverine CR formulation of the present invention avoids plasma level fluctuations accompanied by reduced side effects due to a simplified dosing schedule, thereby improving patient compliance. [Overview of the Initiative]

[0045] The present invention relates to controlled-release (CR) formulations of dorotaberine or a salt thereof or a similar antispasmodic. The formulations of the present invention comprise dorotaberine or a salt thereof, one or more polymers and one or more pharmaceutically acceptable excipients, such that when administered orally, the formulation releases dorotaberine or a salt thereof in a controlled-release (CR) manner over a prolonged period (e.g., 12 to 24 hours). The term “controlled-release” as used throughout the specification shall apply to compositions that modify the release of the active ingredient by any means of dosage form, matrix, particles, coating, part thereof, or any other way. Types of controlled-release include regulated, sustained, sustained-release, extended, delayed, and so on.

[0046] In some embodiments, the present invention relates to once- or twice-daily controlled-release formulations of dorotaberine or its salts that avoid fluctuations in plasma levels, reduce pill burden and side effects, and facilitate a simplified dosing schedule, thereby improving patient compliance. In some embodiments, the formulation immediately releases a sufficient amount of dorotaberine or its salt within the first hour after administration to achieve plasma levels similar to those of conventional IR formulations, thereby rapidly achieving a minimum effective concentration (MEC). The drug is then released gradually over a period of 12 to 24 hours to maintain drug concentrations within the therapeutic concentration range, i.e., within the MEC range.

[0047] In some embodiments, the CR formulations of the present invention utilize polymers from the prior list for film coating of compressed tablets, namely hypromellose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose or its salts, ethylcellulose, carbomer, methacrylic acid, and polyethylene oxide (nonionic polymers), alone or in combination, acrylic copolymers and other tableting excipients, and optionally one or more polymers.

[0048] In some embodiments, the CR formulation of the present invention also includes an acidifying agent. The acidifying agent can be selected alone or in combination from, for example, citric acid, fumaric acid, lactic acid, maleic acid, malic acid, and tartaric acid.

[0049] CR formulations may also contain other pharmaceutically acceptable excipients, including volume extenders, flow aids, and lubricants. Additional components in the developed formulations may also include stabilizers, such as acidifiers and antioxidants.

[0050] Furthermore, similar forms of drug molecules highly sensitive to drotaverine HCl or oxygen may also require encapsulation, special coating, or a microenvironment using an inert gas, such as nitrogen, in the primary packaging of the finished product to further improve shelf life. Preferred examples of drugs prone to oxidative degradation reactions are, but are not limited to, drotaverine, mebeverine, alevarine, papaverine, and pharmaceutically acceptable salts thereof, selected from among them.

[0051] Controlled-release (CR) formulations deliver the drug to the body in a way that establishes a therapeutically effective blood concentration of the active ingredient, and once that concentration is achieved, delivers the drug to the body at the same rate as the body eliminates the drug, thereby maintaining a consistent blood concentration over a long period. By avoiding the peaks and valleys in the blood levels of the active ingredient associated with immediate-release formulations, its controlled drug delivery system reduces the occurrence of adverse effects or side effects. Furthermore, its controlled drug delivery system reduces the frequency of dosing and leads to greater patient convenience in terms of dosing and compliance with the prescribed dosing regimen.

[0052] The present invention also describes a controlled-release (CR) formulation of dorotaverine having a fast-release fraction that allows for a sufficient concentration of the drug, dorotaverine, in the bloodstream to produce a rapid therapeutic effect, and a slow-release fraction that maintains the therapeutic effect. Thus, in some embodiments, the present invention provides a controlled-release formulation of dorotaverine or a salt thereof such that a sufficient amount of the drug is released within about one hour after administration to achieve a minimum effective concentration (MEC) level similar to that of the immediate-release formulation, and the remaining drug is released over a period of about 12 to 24 hours to achieve therapeutic efficiency as a once- or twice-daily drug delivery formulation.

[0053] Furthermore, in some embodiments, the present invention provides a method for preparing controlled-release formulations of dorotaberine or a salt thereof. Also, in some embodiments, the present invention further provides controlled-release formulations of dorotaberine or a salt thereof for the treatment of at least one symptom of gastrointestinal, biliary, urinary and / or gynecological disorders characterized by a spastic state of smooth muscle of the subject.

[0054] Embodiments of the present invention are provided herein: One embodiment of the present invention discloses a controlled-release formulation comprising dorotaberine or a salt thereof, a polymer or a mixture of polymers, and at least one pharmaceutically acceptable excipient, wherein the formulation comprises at least one acidifying agent and 0 to 10% by weight of an antioxidant. In another embodiment, the present invention discloses that the formulation comprises about 10 to about 300 mg of dorotaberine or a salt thereof.

[0055] In yet another embodiment, the present invention discloses that the formulation contains drotaverine or a salt thereof in an amount ranging from 15% to 60% (w / w) of the formulation. In yet another embodiment, the present invention discloses that the drotaverine salt in the formulation is drotaverine hydrochloride. In yet another embodiment, the present invention discloses that at least one acidifying agent in the formulation is selected from the group consisting of citric acid, fumaric acid, lactic acid, maleic acid, malic acid, tartaric acid, and combinations thereof.

[0056] Further embodiments of the present invention disclose that the polymer or mixture of polymers is selected from the group consisting of hypromellose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose or its salts, ethylcellulose, carbomer, methacrylic acid, polyethylene oxide (PEO), and combinations thereof.

[0057] In another embodiment, the present invention discloses that the polymer is polyethylene oxide (PEO). In yet another embodiment, the present invention discloses that the polymer or mixture of polymers is hydroxypropyl methylcellulose having an apparent viscosity ranging from about 100 to 150,000 cP, wherein the polymer or mixture of polymers is optionally K100, K4M, K15M, K100M, E4M, E10M, Methocel K100M CR, or a combination thereof.

[0058] In yet another embodiment, the present invention discloses that the formulation contains a controlled-release polymer in an amount ranging from 0.5% to 30% (w / w) of the formulation. In yet another embodiment, the present invention discloses that at least one pharmaceutically acceptable excipient in the formulation is selected from the group consisting of rubber, fillers, flow aids, lubricants, disintegrants, diluents, binders, lubricants, flow promoters, and combinations thereof.

[0059] In another embodiment, the present invention discloses that the rubber in the formulation is selected from the group consisting of xanthan gum, karaya gum, locust bean gum, alginic acid, sodium alginate, acrylic polymers, and combinations thereof; the diluent is selected from the group consisting of microcrystalline cellulose, lactose, dicalcium phosphate, starch, and combinations thereof; the binder is selected from the group consisting of starch, polyvinylpyrrolidone, natural or synthetic rubber, cellulose polymers, and combinations thereof; the lubricant and flow enhancer is selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate, and combinations thereof; and the disintegrant is selected from the group consisting of sodium starch glycolate, croscarmellose sodium, crospovidone, and combinations thereof.

[0060] In another embodiment, the present invention discloses that the formulation is intended for oral delivery. In yet another embodiment, the present invention discloses that the formulation is a tablet, a minitablet, an MUPS (Multiple Unit Pellet System) tablet, or a capsule.

[0061] In another embodiment, the present invention discloses that the formulation may be in the form of single-layer, double-layer, multi-layer, coated, uncoated, or multi-coated pellets, granules, or beads, which may be filled into capsules or compressed into tablets. In another embodiment, the present invention discloses that the formulation comprises a controlled-release portion and an immediate-release portion. In further embodiments, the present invention discloses that the formulation optionally includes a functional or non-functional coating.

[0062] In another embodiment, the present invention discloses that the tablets or capsules are prepared by a wet granulation, dry granulation / slug tableting, or direct tableting process. In another embodiment, the present invention discloses that the capsule comprises a shell prepared from a gelatin or non-gelatinous substrate.

[0063] In another embodiment, the present invention discloses that the formulation releases dorotaberine or a salt thereof for at least 24 hours. In another embodiment, the present invention discloses that the formulation produces a minimum effective concentration in target plasma similar to that of a conventional immediate-release dosage form within about one hour, and then gradually releases the remaining drug over a period of about 12 to 24 hours, maintaining the drug concentration within the therapeutic range of dorotaverine.

[0064] In yet another embodiment, the present invention discloses that the formulation has an in vitro degradation-release profile of 25% to 40% after about 1 hour, 30% to 50% after about 2 hours, 40% to 65% after about 4 hours, 60% to 85% after about 8 hours, and about 85% or more after about 16 hours.

[0065] One embodiment of the present invention discloses a controlled-release formulation comprising dorotaberine or a salt thereof, a polymer or a mixture of polymers, and at least one pharmaceutically acceptable excipient. In another embodiment, the present invention discloses that the formulation comprises about 10 to about 300 mg of dorotaberine or a salt thereof.

[0066] In yet another embodiment, the present invention discloses that the formulation contains drotaverine or a salt thereof in an amount ranging from 15% to 60% (w / w) of the formulation. In yet another embodiment, the present invention discloses that the drotaverine salt in the formulation is drotaverine hydrochloride.

[0067] In yet another embodiment, the present invention discloses that the polymer or mixture of polymers in the formulation is selected from the group consisting of hypromellose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose or its salts, ethylcellulose, carbomer, methacrylic acid, polyethylene oxide (PEO), and combinations thereof.

[0068] In yet another embodiment, the present invention discloses that the polymer or polymer mixture in the formulation is hydroxypropyl methylcellulose having an apparent viscosity ranging from about 100 to 150,000 cP, wherein the polymer or polymer mixture is optionally K100, K4M, K15M, K100M, E4M, E10M, Methocel K100M CR, or a combination thereof.

[0069] In another embodiment, the present invention discloses that the formulation contains a controlled-release polymer in an amount ranging from 0.5% to 30% (w / w) of the formulation. In a further embodiment, the present invention discloses that at least one pharmaceutically acceptable excipient in the formulation is selected from the group consisting of rubber, fillers, flow aids, lubricants, disintegrants, diluents, binders, lubricants, flow promoters, and combinations thereof.

[0070] In another embodiment, the present invention discloses that the rubber in the formulation is selected from the group consisting of xanthan gum, karaya gum, locust bean gum, alginic acid, sodium alginate, acrylic polymers, and combinations thereof; the diluent is selected from the group consisting of microcrystalline cellulose, lactose, dicalcium phosphate, starch, and combinations thereof; the binder is selected from the group consisting of starch, polyvinylpyrrolidone, natural or synthetic rubber, cellulose polymers, and combinations thereof; the lubricant and flow enhancer is selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate, and combinations thereof; and the disintegrant is selected from the group consisting of sodium starch glycolate, croscarmellose sodium, crospovidone, and combinations thereof.

[0071] In another embodiment, the present invention discloses that the formulation is intended for oral delivery. In yet another embodiment, the present invention discloses that the formulation is a tablet, a minitablet, an MUPS (Multiple Unit Pellet System) tablet, or a capsule.

[0072] In another embodiment, the present invention discloses that the formulation may be in the form of single-layer, double-layer, multi-layer, coated, uncoated, or multi-coated pellets, granules, or beads, which may be filled into capsules or compressed into tablets. In another embodiment, the present invention discloses that the formulation comprises a controlled-release portion and an immediate-release portion. In further embodiments, the present invention discloses that the formulation optionally includes a functional or non-functional coating.

[0073] In another embodiment, the present invention discloses that the formulation produces a minimum effective concentration in target plasma similar to that of a conventional immediate-release dosage form within about one hour, and then gradually releases the remaining drug over a period of about 12 to 24 hours, maintaining the drug concentration within the therapeutic range of dorotaverine.

[0074] In yet another embodiment, the present invention discloses that the formulation has an in vitro degradation-release profile of 25% to 40% after about 1 hour, 30% to 50% after about 2 hours, 40% to 65% after about 4 hours, 60% to 85% after about 8 hours, and about 85% or more after about 16 hours.

[0075] One embodiment of the present invention discloses a method for preparing a monolayer controlled-release tablet containing dorotaberine or a salt thereof, the method being as follows: (a) Dorotaberine or its salt is sieved and dry-mixed with an acidifying agent, polymer and excipient to obtain a drug-excipient mixture; (b) The extragranular components are sieved and mixed with the drug-excipient mixture to obtain the formulation; (c) Compressing the preparation into tablets to form tablets, Includes.

[0076] One embodiment of the present invention discloses a method for preparing monolayer or multilayer tablets containing dorotaberine or a salt thereof, the method being as follows: (a) Drotaberin or its salt is sieved and dry-mixed with an acidifying agent, polymer and excipient to obtain a dry mixture; (b) The dried mixture is granulated using a binder solution containing at least polyvinylpyrrolidone and isopropyl alcohol to obtain granules; (c) Dry the granules to obtain the desired loss on drying of the dried granules; (d) The dried granules are ground into flour and then sieved to obtain granules of a specific size; (e) The extragranular components are sieved and then mixed with granules of a specific size to obtain a formulation; and (f) Compressing the preparation into tablets, Includes.

[0077] In yet another embodiment, the present invention discloses a method for preparing single-layer or multi-layer tablets containing dorotaberine or a salt thereof, which includes coating the tablets with one or more functional or non-functional coatings.

[0078] One embodiment of the present invention discloses a method for treating at least one of the following conditions in a subject requiring the treatment, characterized by a spastic state of smooth muscle: gastrointestinal, biliary, urinary and gynecological disorders, such as irritable bowel syndrome, biliary colic, gallstones, cholecystitis, cholangitis, renal colic, nephrolithiasis, ureteral stones, pyelonephritis, cystitis, dysmenorrhea, threatened miscarriage, or convulsive labor, comprising administering the formulation of the present invention to the subject.

[0079] In another embodiment, the present invention discloses a method for treating at least one symptom of a gastrointestinal, biliary, urinary, and gynecological disorder characterized by a smooth muscle spasticity in a subject requiring the use of the preparation of the present invention, wherein the preparation is administered as a single-layer, double-layer, multi-layer, uncoated, coated, or multi-coated pellet, bead, or granule in the form of a tablet or capsule.

[0080] One embodiment of the present invention discloses the use of the formulation of the present invention for the treatment of at least one symptom of a gastrointestinal, biliary, urinary, or gynecological disorder characterized by a spastic state of smooth muscle in a subject, comprising administering the formulation to the subject. [Brief explanation of the drawing]

[0081] [Figure 1] The figure shows a typical release rate profile of a CR formulation of dorotaberine hydrochloride prepared according to the present invention. The degradation profile is shown as the % drug release of dorotaberine hydrochloride per unit of time (hours). [Modes for carrying out the invention]

[0082] Detailed description of the present invention The broad product line of polymers is available for controlled release (CR) drug delivery formulations / systems, with the application of specialized techniques to meet specific formulation drug delivery requirements, aiding in the development of new products. Controlled release polymers may be one or more hypromellose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose or their salts, ethylcellulose, carbomer, methacrylic acid, and polyethylene oxide (nonionic polymers), and are available in various pharmaceutical grades, offering a wide range of CR properties for various dosage forms and processing methods. Variations in molecular weight and chemical substitution provide countless ways to optimize formulation performance. Each range offers flexibility in controlling the main mechanism of release, with fundamentally different hydrophilic, hydrophobic, wetting, pH-dependent degradation, swelling, and erosion properties.

[0083] In some embodiments, the CR formulation of the present invention includes an acidifying agent. The acidifying agent is selected from, for example, citric acid, fumaric acid, lactic acid, maleic acid, malic acid, and tartaric acid, or a combination thereof.

[0084] In some embodiments, the CR formulation of the present invention comprises dorotaberine or a salt thereof, one or more hydrophilic polymers, and one or more pharmaceutically acceptable additives, such that when administered orally, the formulation releases dorotaberine in a CR manner over a long period of time.

[0085] In some embodiments, the formulations disclosed herein exhibit in vitro degradation characteristics of dorotaverine or its salts, as measured using the USP II method, with approximately 25% to 40% released after approximately 1 hour, approximately 30% to 50% released after approximately 2 hours, approximately 40% to 65% released after approximately 4 hours, and approximately 60% to 85% released after approximately 8 hours, and at least approximately 85% NLT after approximately 16 hours. In some embodiments, the formulations provide a rapid therapeutic effect by releasing a sufficient amount of dorotaverine drug to enable a sufficient concentration of the drug in the bloodstream, followed by a constant and delayed drug release over approximately 16 hours to maintain the effect for a duration of approximately 24 hours. Accordingly, in some embodiments, the present invention provides a controlled-release dosage form in which about 20% of the drug will be released within about one hour, and then about 80% of the remainder will be released to ensure a therapeutic effect over about 24 hours as a once- or twice-daily drug delivery dosage form.

[0086] In some embodiments, the orally controlled-release formulation comprises a low molecular weight polyethylene oxide (PEO) polymer, either alone or in combination with hydroxypropyl methylcellulose (HPMC) accompanied by a nonionic polymer, other tableting excipients, and optionally one or more enteric-coated polymers.

[0087] Therefore, in some embodiments, the CR formulation of the present invention includes the following: • Approximately 10 to 300 mg of dorotaberine or its salts, for example, in the range of 40 to 240 mg. Dorotaberine is preferably present in an amount suitable for once or twice daily administration. • One or more active ingredients that are similar drug molecules in that they are highly susceptible to oxidative degradation. Non-limiting examples of drugs prone to oxidative degradation include drotaverine, mebeverine, alevarine, papaverine, and their pharmaceutically acceptable salts. Disintegrants / superdisintegrants, namely sodium starch glycolate, croscarmellose sodium, and crospovidone, can be selected individually or in combination to improve drug release in the IR layer.

[0088] Polyethylene oxide (PEO) is a nonionic homopolymer of ethylene oxide (CAS registry number 25322-68-3). PEO is chemically similar to polyethylene glycol but has a high molecular weight ranging from 100,000 to 7,000,000 g / mol. Pharmaceutical-grade PEO may possess unique properties such as nonionicity, high swelling, hydrophilicity, and thermoplastic behavior. PEO is a safe and non-toxic polymer that is not absorbed through the gastrointestinal tract. For oral administration, PEO has an IID (Inactive Ingredient Database) limit of approximately 543.9 mg per tablet.

[0089] The "hydrophilic controlled release polymer" is selected from, for example, one or more cellulose derivatives selected from hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, methylcellulose, and sodium carboxymethylcellulose; and rubbers selected from xanthan gum, karaya gum, locust bean gum, alginic acid, sodium alginate, and acrylic polymers. Hydroxypropyl methylcellulose may be a commercially available product such as Methocel® premium product grade having a specific apparent viscosity, e.g., viscosity ranging from about 100 to 150,000 cP (2% in water at 20°C), e.g., K100, K4M, K15M, K100M, E4M, E10M, etc.; or viscosity ranging from 80,000 to 120,000 cP (2% in water at 20°C), e.g., Methocel® K100M CR, etc. The amount of hydrophilic polymer per unit of dorotaberin or its salt has been observed to play a major role in the release characteristics of the formulation. The amount of hydrophilic controlled-release polymer can range from approximately 0.5% to 30% w / w per unit weight of the dosage form.

[0090] The formulation may also contain other release-moderating agents, including hydrophobic polymers in combination with one or more hydrophilic polymers. However, hydrophilic polymers can be used alone or to obtain release-controlled formulations having the desired characteristics achieved by the formulations disclosed herein. The controlled-release formulation may also contain a "pharmaceutically acceptable excipient" selected from, for example, one or more of diluents, binders, lubricants, and flow enhancers.

[0091] For example, the diluent may be selected from one or more of the following: microcrystalline cellulose, lactose, dicalcium phosphate, and starch. The binder may be selected from, for example, one or more of starch, polyvinylpyrrolidone, natural or synthetic rubber, and cellulose polymer. The lubricant and flow promoter may be selected from, for example, one or more of talc, colloidal silicon dioxide, and magnesium stearate.

[0092] To protect dorotaberine hydrochloride from oxidative degradation, the developed formulation contains an acidifying agent. The acidifying agent may be selected from, for example, citric acid alone or in combination with citric acid, fumaric acid, lactic acid, maleic acid, malic acid, and tartaric acid. Antioxidants may be selected from, for example, alone or in combination of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, sodium thiosulfate, propyl gallate, ascorbic acid, and cysteine.

[0093] In some embodiments, CR formulations of dorotaberine or its salts may be obtained in the form of tablets, beads, pellets, or capsules. Tablets may be uncoated tablets, coated tablets, or minitablets. For example, CR formulations may be monolayer matrix tablets, or two-layer, three-layer, or multilayer tablets, with or without functional or non-functional coatings. Functional film coatings are coatings that have a direct effect on the drug release of the API (active drug component) in solid oral dosage forms (e.g., tablets, capsules, granules, or pellets), and examples include ethylcellulose dispersions using soluble polymers or enteric polymer-based dispersions using water-soluble components. Non-functional film coatings, on the other hand, do not have a direct effect on the drug release of the API. Examples include HPMC-based film dispersions, with or without flavorings to enhance the product acceptability of bitter-tasting drugs such as dorotaberine. Tablets may be prepared by wet granulation, dry granulation / slug tableting, or direct tableting processes.

[0094] The raw materials used are selected to ensure the presence of the minimum possible levels of free water (which can be detrimental in causing the degradation of dorotaberine hydrochloride). The manufacturing process, particularly the wet granulation process, requires testing to adjust the level of residual moisture in the final pharmaceutical formulation.

[0095] In some embodiments, the compression tablets may be coated with a suitable film to form the composition. Based on the properties of dorotaberine IR tablets known in the technical field, and based on theories demonstrating the bioavailability and pharmacokinetic properties of dorotaberine in a "once-daily dosage form," the drug release pattern that has not yet been addressed is as follows:

[0096] [Table 1]

[0097] The inventors of the present invention have tested several formulations consisting of CR polymers, fillers, and other pharmaceutical auxiliary components, either alone or in combination, and have attempted dry and wet granulation manufacturing processes to arrive at the CR-releasing formulations of dorotaberine or its salts described above. Initial experiments were conducted as single-layer and double-layer tablet formulations. However, despite conducting several tests, it proved extremely difficult to control the release profile according to the theoretical release patterns evident in Tables 1 and 2 below for single-layer tablets and in Tables 3 and 4 below for double-layer tablets.

[0098] Table 1: Monolayer tablet formulations prepared by various manufacturing processes [Table 2]

[0099] Table 2: Degradation-release profiles of the single-layer tablet formulations in Table 1 [Table 3]

[0100] Table 3: Two-layer tablet formulations [Table 4]

[0101] Table 4: Degradation-release profiles of the two-layer tablet formulations shown in Table 2 [Table 5]

[0102] Subsequently, some of these test batch tablets were subjected to accelerated stability conditions and evaluated for impurity profiling. To understand the chemical degradation characteristics of the CR formulation, the base formulation was subjected to a “forced degradation study,” and the results are presented in Table 5 below. For the samples subjected to accelerated conditions, the presence of unknown impurities was observed at levels of almost 2–3% w / w. Therefore, in order to develop a stable CR formulation with the desired profile, preliminary formulation testing of dorotaberin drug characteristics was performed, and several key physiological and chemical properties were measured, including solubility, degradation, assay and related substance parameters, and drug stability characteristics.

[0103] Table 5: Chemical degradation characteristics of proposed CR formulations used in "Forced / Accelerated Degradation Research" [Table 6]

[0104] The results of the test were the most surprising. Given the fact that dorotaberine is susceptible to oxidation and hydrolysis degradation, it was expected that adding antioxidants would enhance its stability. However, the addition of antioxidants only slightly improved stability. In contrast, and to the inventors' greatest surprise, the addition of acidifying agents resulted in a significant improvement in stability, leading to a controlled-release formulation of dorotaberine. The test demonstrated that incorporating small amounts of antioxidants to obtain a stable CR-release formulation is beneficial in avoiding oxidative degradation reactions of dorotaberine or its salts or active substances prone to oxidation / hydrolysis degradation. Furthermore, the results indicate that the addition of acidulants, either alone or in combination with small amounts of antioxidants, also helps in developing stable CR formulations of dorotaberine or its salts.

[0105] The inventors of the present invention were surprised to find that a stable CR dosage form of dorotaberine or its salts with reduced degradation (and a release profile lasting 12-24 hours) could be achieved solely by the addition of an acidifying agent, and with or without small amounts of antioxidants. The inventors further developed various CR formulations as single-layer or multi-layer; MUPS tablets, coated, and uncoated tablets, as pellets or mini-tablets filled in capsules. These developed tablets may be coated with non-functional or functional coatings. The capsule shell is based on gelatin or non-gelatin polymers. The formulations of the present invention may be tablets or capsules containing immediate and sustained-release portions demonstrating a biphasic drug-release profile. This ensures immediate bioavailability similar to IR tablets (particularly desirable in patients suffering from pain conditions). The IR portion includes a mixture of excipients and stabilizers and a suitable amount of active substance, along with a CR drug portion containing a suitable amount of polymer, excipients and stabilizers, which incorporates a suitable portion of the active substance to ensure controlled drug release over a duration of 12 to 24 hours.

[0106] The present invention provides a controlled-release formulation comprising drotaverine or a salt thereof, at least one acidifying agent, and a polymer or a mixture of polymers, together with a pharmaceutically acceptable excipient, wherein the formulation is substantially free of antioxidants. Antioxidants may be present in the formulation at a concentration of 0-10% (w / w). Exemplary CR formulations of the present invention are shown in Table 6, with the percentage range of each component as in the developed formulation.

[0107] Table 6: Exemplary CR formulations of the present invention [Table 7]

[0108] The developed CR formulation is prepared in various dosage forms, namely tablets or capsules prepared by techniques based on direct mixing, direct tableting, dry granulation, or wet granulation. For the wet granulation manufacturing process, the granulation fluid may be water-alcohol or a non-aqueous granulation fluid, i.e., an alcohol solvent.

[0109] A method for preparing monolayer controlled-release tablets containing a preparation of dorotaberine or a salt thereof comprises: (a) sieving the active ingredient and dry-mixing it with an acidifying agent, a polymer, and an excipient to obtain a drug-excipient mixture; (b) sieving the extragranular components and mixing them with the drug-excipient mixture obtained in step (a); and (c) compressing the preparation from step (b) into tablets to form tablets.

[0110] A method for preparing monolayer or multilayer tablets containing dorotaberine or a salt thereof, the method comprising: (a) sieving the active ingredient and dry mixing it with an acidifying agent, a polymer and an excipient to obtain a dry mixture; (b) granulating the dry mixture with a binder solution containing at least polyvinylpyrrolidone and isopropyl alcohol to obtain granules; (c) drying the granules to obtain a desired loss on drying of the dry granules; (d) grinding the dry granules and then sieving them to obtain granules of a specific size; (e) sieving the extragranular components and then mixing them with the granules obtained in step (d); and (f) compressing the preparation from step (e) into tablets to form tablets. [Examples]

[0111] The following non-limiting examples illustrate CR formulations of dorotaberine or its salts, and processes for producing such formulations.

[0112] Example 1: Dorotaverine CR preparations prepared as "monolayer" tablets by direct compression according to the following method: [Table 8]

[0113] Example 2: Dorotaverine CR preparation prepared as a "single-layer" tablet by the following wet granulation method: [Table 9]

[0114] Example 3: Dorotaberine CR preparation prepared as a "two-layer" tablet by wet granulation: [Table 10]

[0115] Example 4: Dorotaberine CR preparation prepared as a "two-layer" tablet by wet granulation: [Table 11]

[0116] Example 5: Dorotaberine CR preparation prepared as a "two-layer" tablet by wet granulation: [Table 12]

[0117] Optionally, the compressed tablets may be coated with functional and non-functional coatings. Example 6: Dorotaverin CR preparation prepared as a "two-layer" tablet by wet granulation (60 mg strength) [Table 13]

[0118] Example 7: Dorotaverin CR preparation prepared as a "two-layer" tablet by wet granulation (120 mg strength) [Table 14]

[0119] Example 8: Dorotaverin CR preparation prepared as a "two-layer" tablet by wet granulation (180 mg strength) [Table 15]

[0120] Example 9: Dorotaverin CR preparation prepared as a "two-layer" tablet by wet granulation (240 mg strength) [Table 16]

[0121] Example 10: Granules of dorotaberin CR preparation prepared by wet granulation (240 mg strength) [Table 17]

[0122] Example 11: Granules of dorotaberin CR preparation prepared by wet granulation (240 mg strength) [Table 18]

[0123] Example 12: Granules of dorotaberin CR preparation prepared by wet granulation (240 mg strength) [Table 19]

[0124] Example 13: Granules of dorotaberin CR preparation prepared by wet granulation (240 mg strength) [Table 20]

[0125] Example 14: Granules of dorotaberin CR preparation prepared by wet granulation (240 mg strength) [Table 21]

[0126] Example 15: Granules of dorotaberin CR preparation prepared by wet granulation (240 mg strength) [Table 22]

[0127] Example 16: Granules of dorotaberin CR preparation prepared by wet granulation (240 mg strength) [Table 23]

[0128] Example 17: Granules of dorotaberin CR preparation prepared by wet granulation (240 mg strength) [Table 24]

[0129] Example 18: Drotaberine CR formulation MUPS (Multiple Unit Pellet System) tablets (240 mg strength) [Table 25]

[0130] Example 19: Capsules of Drotaverin CR preparation containing CR pellets (240 mg strength) [Table 26]

[0131] Degradation characteristics in vitro The formulations of the present invention are not limited thereto, but are illustrated in the examples previously shown herein. A typical drug elution rate profile of an exemplary formulation of the present invention is shown in Figure 1. The developed formulations were evaluated for "in vitro degradation characteristics" using the USP II method at 75 rpm in 1000 ml of 0.1 N HCl (pH 1.2) at 37 ± 0.5 °C. The in vitro degradation release profile of the CR formulation of the present invention was found to be approximately 25% to 40% released after approximately 1 hour, approximately 30% to 50% released after approximately 2 hours, approximately 40% to 65% released after approximately 4 hours, approximately 60% to 85% released after approximately 8 hours, and approximately 85% of the NLT released after approximately 16 hours.

[0132] Chemical stability: Impurities in new drug products, such as degradation products or reaction products of the active pharmaceutical ingredient (API) accompanied by excipients and / or an immediate container closure system, are collectively referred to as "degradation products." In most cases, the presence of impurities in a new API does not need to be observed or indicated in the new drug product unless they are also degradation products.

[0133] The present invention provides a stable CR formulation of dorotaberine or its salts or similar active substances that are prone to oxidative / hydrolytic degradation. The developed formulation has improved chemical stability, where the level of individual unknown impurities is less than 0.2% w / w (according to currently available globally acceptable standards for drug products).

[0134] Non-limiting advantages of the CR formulation of the present invention: 1. Through extensive testing and the development of effective ratios of polymers, binders, and excipients to the active drug, the CR formulation of dorotaberine achieves target drug release from a single, ingestible dosage form and sustains the target MEC for approximately 24 hours.

[0135] 2. The CR formulations disclosed herein are designed to achieve an immediate onset of action and a sustained-release profile. For example, a sufficient (therapeutic) dose of dorotaverine is released within approximately one hour after administration to achieve plasma levels similar to those of an immediate-release formulation, while the remaining drug is gradually released over a period of approximately 12–24 hours to maintain drug concentrations within the therapeutic range.

[0136] 3. Dorotaberine CR formulations can be formulated as single-layer or multi-layer tablets, multi-coated mini-tablets, or pellets or beads filled within capsules.

[0137] 4. Dorotaberine preparations can be manufactured by direct compression, dry granulation, wet granulation, or fluidized bed processing.

[0138] Other embodiments of the present invention will be apparent to those skilled in the art from the considerations of the specification and the practice of the embodiments disclosed herein. The specification and examples are intended to be merely illustrative, given the true scope and gist of the invention as set forth by the following claims. In addition, where this application lists steps of a method or procedure in a particular order, it may be possible to change the order in which several steps are performed, or even be advantageous in certain circumstances, and the particular steps of the claims of such methods or procedures described herein below are not intended to be considered order-specific unless such order specificity is explicitly stated in the claim.

Claims

1. A controlled-release formulation comprising dorotaberine or a salt thereof, a polymer or a mixture of polymers, and at least one pharmaceutically acceptable excipient, wherein the formulation comprises at least one acidifying agent and 0 to 10% by weight of an antioxidant.

2. The formulation according to claim 1, wherein the formulation comprises about 10 to about 300 mg of dorotaberine or a salt thereof.

3. The formulation according to claim 1 or 2, wherein the formulation contains dorotaberine or a salt thereof in an amount of 15% to 60% (w / w) of the formulation.

4. The formulation according to any one of claims 1 to 3, wherein the dorotaberine salt is dorotaberine hydrochloride.

5. The formulation according to claim 1, wherein the at least one acidifying agent is selected from the group consisting of citric acid, fumaric acid, lactic acid, maleic acid, malic acid, tartaric acid, and combinations thereof.

6. The formulation according to claim 1, wherein the polymer or mixture of polymers is selected from the group consisting of hypromellose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose or its salts, ethylcellulose, carbomer, methacrylic acid, polyethylene oxide (PEO), and combinations thereof.

7. The formulation according to claim 6, wherein the polymer is polyethylene oxide (PEO).

8. The formulation according to claim 6, wherein the polymer or mixture of polymers is hydroxypropyl methylcellulose having an apparent viscosity ranging from about 100 to 150,000 cP, wherein optionally the polymer or mixture of polymers is K100, K4M, K15M, K100M, E4M, E10M, Methocel K100M CR, or a combination thereof.

9. The formulation according to any one of claims 1 to 8, wherein the formulation contains a controlled-release polymer in an amount of 0.5% to 30% (w / w) of the formulation.

10. The formulation according to claim 1, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of rubber, bulking agents, flow aids, lubricants, disintegrants, diluents, binders, lubricants, flow promoters, and combinations thereof.

11. The formulation according to claim 10, wherein the rubber is selected from the group consisting of xanthan gum, karaya gum, locust bean gum, alginic acid, sodium alginate, acrylic polymers, and combinations thereof; the diluent is selected from the group consisting of microcrystalline cellulose, lactose, dicalcium phosphate, starch, and combinations thereof; the binder is selected from the group consisting of starch, polyvinylpyrrolidone, natural or synthetic rubber, cellulose polymers, and combinations thereof; the lubricant and flow promoter are selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate, and combinations thereof; and the disintegrant is selected from the group consisting of sodium starch glycolate, croscarmellose sodium, crospovidone, and combinations thereof.

12. The formulation according to any one of claims 1 to 11, wherein the formulation is for oral delivery.

13. The formulation according to claim 12, wherein the formulation is a tablet, a minitablet, an MUPS (Multiple Unit Pellet System) tablet, or a capsule.

14. The formulation according to claim 13, wherein the formulation is in the form of a single-layer, double-layer, multi-layer, coated, uncoated, or multi-coated pellet, granule, or bead, which can be filled into a capsule or compressed into a tablet.

15. The formulation according to any one of claims 1 to 14, wherein the formulation comprises a controlled-release portion and an immediate-release portion.

16. The formulation according to any one of claims 1 to 15, wherein the formulation optionally includes a functional or non-functional coating.

17. The formulation according to any one of claims 13 to 16, wherein the aforementioned tablets or capsules are prepared by a wet granulation, dry granulation / slug tableting, or direct tableting process.

18. The formulation according to any one of claims 13 to 17, wherein the capsule comprises a shell prepared from gelatin or a non-gelatinous base material.

19. The formulation according to any one of claims 1 to 18, wherein the formulation releases dorotaverine or a salt thereof for at least 24 hours.

20. The formulation according to any one of claims 1 to 19, wherein the formulation produces a minimum effective concentration in the target plasma similar to that of an immediate-release formulation within about one hour, and then gradually releases the remaining drug over a period of about 12 to 24 hours to maintain the drug concentration within the therapeutic concentration range of dorotaverine.

21. The formulation according to any one of claims 1 to 20, wherein the formulation has an in vitro degradation-release profile of 25% to 40% after about 1 hour, 30% to 50% after about 2 hours, 40% to 65% after about 4 hours, 60% to 85% after about 8 hours, and about 85% or more after about 16 hours.

22. A controlled-release formulation comprising dorotaberine or a salt thereof, a polymer or a mixture of polymers, and at least one pharmaceutically acceptable excipient.

23. The formulation according to claim 22, wherein the formulation comprises about 10 to about 300 mg of dorotaberine or a salt thereof.

24. The formulation according to claim 23, wherein the formulation contains dorotaberine or a salt thereof in an amount of 15% to 60% (w / w) of the formulation.

25. The formulation according to any one of claims 22 to 24, wherein the dorotaberine salt is dorotaberine hydrochloride.

26. The formulation according to claim 22, wherein the polymer or mixture of polymers is selected from the group consisting of hypromellose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose or its salts, ethylcellulose, carbomer, methacrylic acid, polyethylene oxide (PEO), and combinations thereof.

27. The formulation according to claim 26, wherein the polymer or mixture of polymers is hydroxypropyl methylcellulose having an apparent viscosity ranging from about 100 to 150,000 cP, wherein optionally the polymer or mixture of polymers is K100, K4M, K15M, K100M, E4M, E10M, Methocel K100M CR, or a combination thereof.

28. The formulation according to any one of claims 22 to 27, wherein the formulation contains a controlled-release polymer in an amount of 0.5% to 30% (w / w) of the formulation.

29. The formulation according to claim 22, wherein the at least one pharmaceutically acceptable excipient is selected from the group consisting of rubber, bulking agents, flow aids, lubricants, disintegrants, diluents, binders, lubricants, flow promoters, and combinations thereof.

30. The formulation according to claim 29, wherein the rubber is selected from the group consisting of xanthan gum, karaya gum, locust bean gum, alginic acid, sodium alginate, acrylic polymers, and combinations thereof; the diluent is selected from the group consisting of microcrystalline cellulose, lactose, dicalcium phosphate, starch, and combinations thereof; the binder is selected from the group consisting of starch, polyvinylpyrrolidone, natural or synthetic rubber, cellulose polymers, and combinations thereof; the lubricant and flow promoter are selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate, and combinations thereof; and the disintegrant is selected from the group consisting of sodium starch glycolate, croscarmellose sodium, crospovidone, and combinations thereof.

31. The formulation according to any one of claims 22 to 30, wherein the formulation is for oral delivery.

32. The formulation according to claim 31, wherein the formulation is a tablet, a minitablet, an MUPS (Multiple Unit Pellet System) tablet, or a capsule.

33. The formulation according to claim 32, wherein the formulation is in the form of a single-layer, double-layer, multi-layer, coated, uncoated, or multi-coated pellet, granule, or bead, which can be filled into a capsule or compressed into a tablet.

34. The formulation according to any one of claims 22 to 33, wherein the formulation comprises a controlled-release portion and an immediate-release portion.

35. The formulation according to any one of claims 22 to 34, wherein the formulation optionally includes a functional or non-functional coating.

36. The formulation according to any one of claims 22 to 35, wherein the formulation produces a minimum effective concentration in the target plasma similar to that of an immediate-release formulation within about one hour, and then gradually releases the remaining drug over a period of about 12 to 24 hours to maintain the drug concentration within the therapeutic concentration range of dorotaverine.

37. The formulation according to any one of claims 22 to 36, wherein the formulation has an in vitro degradation-release profile of 25% to 40% after about 1 hour, 30% to 50% after about 2 hours, 40% to 65% after about 4 hours, 60% to 85% after about 8 hours, and about 85% or more after about 16 hours.

38. A method for preparing monolayer controlled-release tablets containing dorotaberine or a salt thereof, the following: (a) Dorotaberine or its salt is sieved and dry-mixed with an acidifying agent, polymer and excipient to obtain a drug-excipient mixture; (b) The extragranular components are sieved and mixed with the drug-excipient mixture to obtain the formulation; (c) Compressing the above preparation into tablets to form tablets, A method that includes this.

39. A method for preparing monolayer or multilayer tablets containing dorotaberine or a salt thereof, the following: (a) Dorotaberin or its salt is sieved and dry-mixed with an acidifying agent, polymer and excipient to obtain a dry mixture; (b) The dried mixture is granulated using a binder solution containing at least polyvinylpyrrolidone and isopropyl alcohol to obtain granules; (c) Dry the granules to obtain the desired loss on drying of the dried granules; (d) The dried granules are ground into flour and then sieved to obtain granules of a specific size; (e) The extragranular components are sieved and then mixed with granules of a specific size to obtain a formulation; and (f) Compressing the preparation into tablets, A method that includes this.

40. The method according to claim 38 or 39, further comprising coating the tablet with one or more functional or non-functional coatings.

41. A method for treating at least one of the following conditions characterized by a spastic state of smooth muscle in a subject in need of the preparation described in any one of claims 1 to 21 or 22 to 37: gastrointestinal, biliary, urinary and gynecological disorders, such as irritable bowel syndrome, biliary colic, gallstones, cholecystitis, cholangitis, renal colic, nephrolithiasis, ureteral stones, pyelonephritis, cystitis, dysmenorrhea, threatened miscarriage, or convulsive labor.

42. The method according to claim 41, wherein the formulation is administered as a single-layer, double-layer, multi-layer, uncoated, coated, or multi-coated pellet, bead, or granule in the form of a tablet or capsule.

43. Use of the preparation according to any one of claims 1 to 21 or 22 to 37, comprising administering the preparation to a subject, for the treatment of at least one symptom of a gastrointestinal, biliary, urinary, or gynecological disorder characterized by a spastic state of smooth muscle of the subject.

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