Pharmaceutical combination of anticonvulsants and anxiolytics

Abstract

The present disclosure provides fixed dose combinations of drotaverine or a salt thereof and a benzodiazepine, methods for preparing the fixed dose combinations, and their use in therapy.

Description

[Technical field]

[0001] The present disclosure relates to a pharmaceutical combination of an anticonvulsant and an anxiolytic. The present disclosure provides a stable formulation comprising drotaverine and chlordiazepoxide or a salt thereof. The present disclosure also relates to a method for preparing such a combination and formulation, and its use. [Background technology]

[0002] Irritable bowel syndrome (IBS) is a common functional bowel disorder characterized by recurrent abdominal pain primarily associated with defecation and changes in stool form or frequency. IBS is classified into four subtypes based on abnormal bowel habits: diarrhea-predominant IBS (IBS-D), constipation-predominant IBS (IBSC), mixed IBS (IBS-M), or unclassified IBS. Approximately 10% of the world's population suffers from some form of IBS.

[0003] The exact cause of IBS is still unknown, but several mechanisms have been suggested. Symptoms may result from disturbances in the way the digestive tract, brain, and nervous system interact. This can cause changes in normal bowel movements and sensations. At least half of IBS patients are said to be depressed, anxious, or hypochondriac, as IBS is a disorder of intestinal motility and sensation and is exacerbated by psychosocial stressors. In IBS patients, abdominal pain is almost ubiquitous and greatly impacts the patient's quality of life. A report by a task force of the Indian Society of Gastroenterology revealed that as many as 70% of IBS patients have abdominal pain or discomfort.

[0004] Traditionally, abdominal pain has been believed to be caused by spasms of smooth muscles. For this reason, antispasmodics have been the mainstay of treatment. Antispasmodics relax the smooth muscles of the gastrointestinal tract and reduce their contractile force. IBS patients usually experience increased colonic motility in response to meals (gastric relaxation reflex), which can be accompanied by diarrhea and spasms.

[0005] When bowel-directed therapy for diarrhea or constipation is insufficient, or pain is a prominent symptom, treatment with antispasmodics is generally useful, especially for postprandial symptoms. Antispasmodics may inhibit excessive contractions after meals. Randomized trial data show that antispasmodics reduce overall symptoms and reduce pain. Because IBS is a disorder of intestinal motility and sensation, and is exacerbated by psychosocial stressors, treatment is most effective when a multicomponent comprehensive approach is used. In fact, treatments for IBS are generally directed at gastrointestinal motility, gastrointestinal sensation, or central nervous system processing.

[0006] Drotaverine is an antispasmodic, well tolerated, and available in over 42 countries worldwide. Drotaverine has antispasmodic and vasodilatory properties. It exerts its antispasmodic action by inhibiting phosphodiesterase activity. Drotaverine has a rapid onset of action, beginning to relieve pain within 12 minutes. Drotaverine is an effective antispasmodic without anticholinergic side effects. Drotaverine is used to relieve IBS pain. Drotaverine relieves IBS spasms and normalizes smooth muscle contraction through its unique site-specific action. It does not cause constipation and is suitable for all types of IBS (diarrhea-predominant IBS, constipation-predominant IBS, unclassifiable IBS, and mixed IBS). Drotaverine is available as 40 mg and 80 mg tablets. The usual adult dose of drotaverine is 120-240 mg per day (2-3 divided doses).

[0007] In pharmacokinetic and bioavailability studies, drotaverine was rapidly absorbed, with onset of action within 12 minutes and drug absorption from the small intestine of approximately 90% after oral administration of an 80 mg IR tablet. Peak plasma concentrations were achieved after 1-3 hours, with elimination half-lives ranging from 7-11.95 hours. Toxicological studies showed that the oral LD 50 has been reported to be >1000 mg / Kg body weight, and drotaverine has a wide therapeutic index.

[0008] Anxiolytics are drugs that affect the whole body, including mood and the digestive system. Benzodiazepines are a type of anxiolytic drug.

[0009] Chlordiazepoxide hydrochloride is a benzodiazepine with anxiolytic, sedative, appetite-stimulating, and weak analgesic properties. It acts by enhancing the activity of the chemical messenger (GABA) that inhibits abnormal and excessive activity of nerve cells in the brain. The mechanism of action involves the drug binding to the stereospecific benzodiazepine binding site of GABA receptors at multiple sites in the central nervous system, resulting in increased binding of the inhibitory neurotransmitter GABA to GABA(A) receptors. As a result, benzodiazepines enhance GABA-mediated chloride influx, causing membrane hyperpolarization. The neuroinhibitory effects result in sedative, hypnotic, anxiolytic, and muscle relaxant effects. Chlordiazepoxide is one of the safer and more effective psychopharmacological compounds available, as demonstrated by extensive clinical evidence. Chlordiazepoxide is available as capsules containing 5 mg, 10 mg, or 25 mg of chlordiazepoxide HCl.

[0010] It takes several hours for the blood concentration of chlordiazepoxide HCl to reach its peak, and the half-life is 24-48 hours. After discontinuation of administration, the plasma concentration declines slowly over several days. 1-2% of the drug is excreted in the urine as unchanged, and 3-6% as conjugated forms.

[0011] The currently recommended dosing schedules for drotaverine and chlordiazepoxide are three tablets per day and six tablets per day, respectively, when patients are prescribed both drugs. The number of tablets per day often directly affects patient compliance. Combining both drugs into one tablet can reduce the pill burden of both drugs and increase patient compliance. The use of combination formulations is an emerging method to reduce pill burden, especially in patients with multiple chronic diseases. By reducing the overall pill burden and simplifying the drug dosing regimen, fixed combinations have been shown in several studies to improve medication adherence. However, it is difficult to mix different active ingredients that maintain efficacy without compromising stability.

[0012] A fixed dose combination (FDC) is defined as a combination of two or more active pharmaceutical ingredients or compounds, regardless of their dosage form. Each drug in an FDC has an independent mechanism of action, providing synergistic, additive, or complementary pharmacological effects. IBS patients frequently experience various comorbidities that contribute to their disease burden and are likely to be prescribed multiple medications. However, keeping track of the dosing schedules of multiple medications can be a burden for these patients. This can reduce patient compliance with approved dosing schedules, which in turn can lead to reduced efficacy of the medications.

[0013] FDCs containing a combination of antispasmodic and anxiolytic drugs may be useful for patients with anxiety or intractable abdominal pain. Therefore, formulations combining other drugs have been introduced and are generally accepted. One combination used for the treatment of IBS consists of clidinium bromide / mebeverine (antispasmodic) and chlordiazepoxide (anxiolytic). In addition, it is known to use drotaverine / mebeverine HCL or chlordiazepoxide alone in the treatment of functional gastrointestinal disorders. However, FDCs of drotaverine and benzodiazepines are not known in the art.

[0014] Some possible combinations of antispasmodics with other drugs have been studied in the following literature:

[0015] Indian patent application 5678 / CHE / 2014 discloses a fixed dose pharmaceutical formulation of an analgesic and an antispasmodic (drotaverine). WO2019149917 relates to a pharmaceutical composition comprising metamizole, drotaverine and caffeine. Indian patent application 2208 / MUM / 2013 discloses a FDC of mebeverine and one or more anti-inflammatory drugs. WO2016041036 relates to a pharmaceutical composition comprising an analgesic (ketorolac tromethamine) and an antispasmodic being hyoscytium, pargeverine, tolterodine, mebeverine or papaverine.

[0016] The present disclosure includes a FDC of drotaverine as an antispasmodic and chlordiazepoxide (CDO), an anxiolytic drug, which is an attractive solution for effectively relieving symptoms of anxiety and tension in the spastic colon and associated gastrointestinal tract. Due to different mechanisms of action, the combination of the two drugs can provide comprehensive and rapid relief of pain, spasms, and / or anxiety in IBS patients.

[0017] Therefore, the inventors of the present disclosure carried out an experimental study to mix drotaverine as an antispasmodic and chlordiazepoxide as an anxiolytic. However, when chlorazepoxide and drotaverine were mixed, their significant decomposition was observed. The details of the carried out experiment and the obtained results are described below.

[0018] There is a need in the art for a drug delivery format that allows these two classes of drugs to be formulated in a single tablet as an FDC for ease of administration and improved patient compliance. There is a need for chemically stable pharmaceutical combinations or formulations that contain the active agents drotaverine and chlordiazepoxide.

[0019] There is also a need in the art for a method of providing suitable pharmaceutical packaging for FDC formulations containing chlordiazepoxide or a pharma- ceutically acceptable salt thereof and drotaverine or a pharma- ceutically acceptable salt thereof. The use of packaging formats also impacts the stability of these pharmaceutical dosage forms, allowing for longer shelf lives. Summary of the Invention

[0020] In some embodiments, the present disclosure provides an FDC comprising drotaverine or a pharma- ceutically acceptable salt thereof and a benzodiazepine. In some embodiments, the present disclosure provides an FDC comprising drotaverine or a pharma- ceutically acceptable salt thereof and chlordiazepoxide or a pharma- ceutically acceptable salt thereof. In some embodiments, the FDC comprises a core and a coating surrounding the core, the core comprising at least one layer. In some embodiments, the core comprises drotaverine or a pharma- ceutically acceptable salt thereof and the coating surrounding the core comprises chlordiazepoxide or a pharma- ceutically acceptable salt thereof. In some embodiments, the core comprises at least two layers, the first layer comprising drotaverine or a pharma- ceutically acceptable salt thereof and the second layer comprising chlordiazepoxide or a pharma- ceutically acceptable salt thereof. In some embodiments, the core further comprises a third layer, said third layer being between the first layer comprising drotaverine or a pharma- ceutically acceptable salt thereof and the second layer comprising chlordiazepoxide or a pharma- ceutically acceptable salt thereof, said third layer comprising an inert excipient.

[0021] In some embodiments, the disclosure provides an FDC comprising 20-300 mg of drotaverine or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharma- ceutically acceptable salt of drotaverine is drotaverine hydrochloride. In some embodiments, the FDC comprises 2.5-40 mg of chlordiazepoxide or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharma- ceutically acceptable salt of chlordiazepoxide is chlordiazepoxide hydrochloride.

[0022] In some embodiments, the present disclosure provides a FDC comprising a coating agent, the coating agent comprising polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, dextrin, maltodextrin, lactose, D-mannitol, polyvinyl alcohol polymer, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, or ethyl acrylate methyl methacrylate copolymer, or a combination thereof. In some embodiments, the coating agent further comprises a plasticizer, an anti-blocking agent, an opacifier, a colorant, or a combination thereof.

[0023] In some embodiments, the present disclosure provides FDCs comprising an acidifier, an antioxidant, a diluent, a binder, a surfactant, a lubricant, or a glidant, or a combination thereof. In some embodiments, the acidifier comprises citric acid, fumaric acid, lactic acid, maleic acid, malic acid, or tartaric acid, or a combination thereof. In some embodiments, the antioxidant comprises butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, sodium thiosulfate, propyl gallate, ascorbic acid, or cysteine, or a combination thereof. In some embodiments, the diluent comprises lactose monohydrate, anhydrous lactose, mannitol, corn starch, corn starch, pregelatinized starch, starch 1500, microcrystalline cellulose, powdered cellulose, directly compressible grade cellulose, sorbitol, xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, or tribasic calcium phosphate, or a combination thereof. In some embodiments, the binder comprises hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, copovidone, powdered acacia, gelatin, guar gum, carbomer, methylcellulose, polymethacrylate, or starch, or a combination thereof. In some embodiments, the surfactant comprises polyoxyethylene-polyoxypropylene block copolymer, alkyl sulfate, alkylaryl sulfonate, polyethylene glycol, or polysorbate, or a combination thereof. In some embodiments, the lubricant comprises magnesium stearate, glyceryl monostearate, palmitic acid, talc, carnauba wax, calcium stearate, sodium stearate, sodium lauryl sulfate, magnesium lauryl sulfate, zinc stearate, polyoxymethylene monostearate, calcium silicate, silicon dioxide, a hydrogenated vegetable oil or fat, stearic acid, or glyceryl behenate, or a combination thereof. In some embodiments, the glidant comprises colloidal silicon dioxide or talc, or a combination thereof.

[0024] In some embodiments, the disclosure provides an FDC prepared using a direct compression process. In some embodiments, the FDC is prepared using a dry granulation process. In some embodiments, the FDC is prepared using a wet granulation process. In some embodiments, the FDC is prepared using a fluidized bed process. In some embodiments, the FDC is packaged with a pharma- ceutically acceptable desiccant. In some embodiments, the FDC is packaged in an inert gas environment. In some embodiments, the FDC exhibits acceptable chemical stability for 6 months according to ICH guidelines.

[0025] In some embodiments, the disclosure provides an FDC comprising drotaverine hydrochloride, chlordiazepoxide, and citric acid, the formulation comprising a bilayer core having a coating, the drotaverine hydrochloride being in a first layer of the core and the chlordiazepoxide being in a second layer of the core. In some embodiments, the FDC is prepared using a dry granulation process.

[0026] In some embodiments, the disclosure provides a method for preparing an FDC of drotaverine or a pharma- ceutically acceptable salt thereof and chlordiazepoxide or a pharma- ceutically acceptable salt thereof, comprising a core having a coating, using a direct compression process, the method comprising: mixing intragranular ingredients for the core of the FDC; loading the intragranular ingredients into a tablet press; compressing the intragranular ingredient mixture to form the core of the FDC; and coating the core with the weight of the coat until the weight of the coat is 1-5% of the weight of the FDC.

[0027] In some embodiments, the disclosure provides a method for preparing an FDC of drotaverine or a pharma- ceutically acceptable salt thereof and chlordiazepoxide or a pharma- ceutically acceptable salt thereof, comprising a core having a coating, using a dry granulation process, the method comprising: mixing intragranular ingredients for the core of the FDC; slugging or compressing the intragranular ingredient mixture to obtain compacts; milling and sieving the compacts to obtain a sieved granule; mixing the sieved granule with at least one excipient to obtain a final blend; loading the final blend into a tablet press; compressing the final blend to form the core of the FDC; and coating the core with a coating until the weight of the coating is 1-5% of the weight of the FDC.

[0028] In some embodiments, the disclosure provides a method for preparing an FDC of drotaverine or a pharma- ceutically acceptable salt thereof and chlordiazepoxide or a pharma-ceutically acceptable salt thereof, comprising a core having a coating, using a wet granulation process, the method comprising: mixing intragranular ingredients for the core of the FDC; shearing the intragranular ingredient mixture with a binder solution using a rapid mixer granulator to obtain granules; drying the granules to obtain dry granules; mixing the dry granules with at least one excipient to obtain a final blend; loading the final blend into a tablet press; compressing the final blend to form a tablet core; and coating the core with a coating until the weight of the coating is 1-5% of the weight of the FDC.

[0029] In some embodiments, the disclosure provides a method for preparing an FDC of drotaverine or a pharma- ceutically acceptable salt thereof and chlordiazepoxide or a pharma- ceutically acceptable salt thereof, comprising a core having a coating, using a fluidized bed process, the method comprising: mixing intragranular ingredients for the core of the FDC; forming granules from the mixed intragranular ingredients and a binder solution by fluidized bed granulation; drying the granules to obtain dry granules; mixing the dry granules with at least one excipient to obtain a final blend; loading the final blend into a tablet press; compressing the final blend to form the core of the FDC; and coating the core with a coating until the weight of the coating is 1-5% of the weight of the FDC.

[0030] In some embodiments, the disclosure provides a method for preparing an FDC comprising drotaverine or a pharma- ceutically acceptable salt thereof and chlordiazepoxide or a pharma- ceutically acceptable salt thereof comprising a multi-layered core having a coating using a direct compression process, the method comprising: separately mixing the intragranular ingredients for each layer of the core; loading a separate final blend for each layer of the core into a tablet press; compressing the separate final blends to form a multi-layered core of the FDC; and coating the core with the coating until the weight of the coating is 1-5% of the weight of the fixed dose combination.

[0031] In some embodiments, the disclosure provides a method for preparing an FDC comprising drotaverine or a pharma- ceutically acceptable salt thereof and chlordiazepoxide or a pharma- ceutically acceptable salt thereof, comprising a multi-layered core having a coating, using a dry granulation process, the method comprising: blending intragranular ingredients for each layer of the core; slugging or compressing the separate intragranular ingredient blends to obtain compacts for each layer of the core; milling and sieving the separate compacts to obtain sieved granules for each layer of the core; blending the separate sieved granules with at least one excipient to obtain a final blend for each layer of the core; loading the separate final blends for each layer of the core into a tablet press; compressing the separate final blends to form the multi-layered core of the FDC; and coating the core with the coating until the weight of the coating is 1-5% of the weight of the FDC.

[0032] In some embodiments, the disclosure provides a method for preparing an FDC of drotaverine or a pharma- ceutically acceptable salt thereof and chlordiazepoxide or a pharma- ceutically acceptable salt thereof, comprising a multi-layered core having a coating, using a wet granulation process, the method comprising: mixing intragranular ingredients for each layer of the multi-layered core; shearing the separate intragranular ingredient mixtures with a binder solution using a rapid mixer granulator to obtain granules for each layer of the core; drying the separate granules to obtain dry granules for each layer of the core; mixing the separate dry granules with at least one excipient to obtain a final blend for each layer of the core; loading the separate final blends for each layer of the core into a tablet press; compressing the final blends to form the multi-layered core of the FDC; and coating the core with the coating until the weight of the coating is 1-5% of the weight of the FDC.

[0033] In some embodiments, the disclosure provides a method for preparing an FDC of drotaverine or a pharma- ceutically acceptable salt thereof and chlordiazepoxide or a pharma- ceutically acceptable salt thereof comprising a multi-layered core having a coating using a fluidized bed process, the method comprising: mixing intragranular ingredients for each layer of the core; forming granules from the mixed intragranular ingredients and a binder solution by fluidized bed granulation; drying the separate granules to obtain dried granules for each layer of the core; mixing the separate dried granules with at least one excipient to obtain a final blend for each layer of the core; loading the separate final blends for each layer of the core into a tablet press; compressing the final blends to form a multi-layered core of the FDC; and coating the core with the coating until the weight of the coating is 1-5% of the weight of the FDC.

[0034] In some embodiments, the present disclosure provides a method for treating at least one symptom of a gastrointestinal disorder characterized by a spastic state of smooth muscle in a subject in need thereof.Specific exemplary conditions that may be treated according to some embodiments include treating irritable bowel syndrome (irritable colon, spastic colon, mucous colitis), treating gastrointestinal manifestations of anxiety and tension in the gastrointestinal tract, treating abdominal pain, or treating gastrointestinal spasms secondary to organic diseases of the digestive system, such as gastric and duodenal ulcers, acute enteritis, etc.

[0035] In some embodiments, the present disclosure provides a pharmaceutical composition for use in treating at least one symptom of gastrointestinal disorder characterized by smooth muscle spasticity in a subject in need thereof.In some embodiments, the pharmaceutical composition is used for treating irritable bowel syndrome (irritable colon, spastic colon, mucous colitis), treating symptoms of gastrointestinal anxiety and tension in the gastrointestinal tract, treating abdominal pain, or gastrointestinal spasm secondary to organic diseases of the digestive system, such as gastroduodenal ulcer, acute enteritis, or combinations thereof.

[0036] In some embodiments, the present disclosure provides a combination comprising drotaverine or a pharma- ceutically acceptable salt thereof and at least one benzodiazepine formulated as a single medicine. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] Detailed Description In some aspects, the present disclosure relates to pharmaceutical FDCs of anticonvulsants and anxiolytics, and / or one or more pharma- ceutically acceptable excipients. In some embodiments, the combination is an FDC suitable for oral administration. In one embodiment, the present disclosure relates to chemically stable pharmaceutical formulations comprising drotaverine and chlordiazepoxide or their pharma- ceutically acceptable salts and one or more pharma-ceutically acceptable excipients and their use.

[0038] In some embodiments, the disclosure describes novel stable FDCs. In some embodiments, the novel pharmaceutical compositions are chemically stable and bioavailable FDC products. Based on accelerated stability data, certain FDC formulations have significantly reduced chemical degradation when formulated as FDCs of single-layered, bi-layered, or multi-layered active agents. In some embodiments, the dosage form is a "tablet in tablet" or "compression coated tablet", "tablet in capsules", "multi-layered tablet", "drug coated pellet", or "mini-tablets filled in capsules". In some embodiments, the dosage form is a tablet compressed or coated into a hard capsule, multi-layered tablet, or compression coated tablet. In some embodiments, the dosage form does not have a coating. In some embodiments, the tablet has a coating.

[0039] In some embodiments, the disclosure provides an FDC that includes an anxiolytic and an anticonvulsant and one or more pharma- ceutically acceptable excipients.

[0040] In some embodiments, the disclosure relates to an FDC comprising chlordiazepoxide, drotaverine, and one or more pharma- ceutically acceptable excipients.

[0041] In some embodiments, the disclosure relates to an FDC comprising chlordiazepoxide, drotaverine, and one or more pharma- ceutically acceptable excipients including a filler, binder, stabilizer, antioxidant, disintegrant, lubricant, or coating material, or a combination thereof.

[0042] In some embodiments, the present disclosure relates to an FDC comprising chlordiazepoxide, drotaverine, and a pharma- ceutically acceptable excipient comprising an acidifying agent.

[0043] In some embodiments, the disclosure relates to an FDC comprising chlordiazepoxide, drotaverine, and a pharma- ceutically acceptable excipient comprising an acidifying agent comprising citric acid, fumaric acid, lactic acid, maleic acid, malic acid, or tartaric acid, or a combination thereof.

[0044] In some embodiments, the disclosure relates to an FDC comprising chlordiazepoxide, drotaverine, and a pharma- ceutically acceptable excipient comprising an antioxidant.

[0045] In some embodiments, the disclosure relates to a FDC comprising chlordiazepoxide, drotaverine, and a pharma- ceutically acceptable excipient comprising an antioxidant comprising butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, sodium thiosulfate, propyl gallate, ascorbic acid, or cysteine, or a combination thereof.

[0046] In some embodiments, the disclosure relates to an FDC of chlordiazepoxide and drotaverine, and one or more pharma- ceutically acceptable excipients, wherein the pharmaceutical formulation comprises a core having one or more layers and a coating surrounding the core, for use in treating irritable bowel syndrome (irritable colon, spastic colon, mucosal colitis), treating GI anxiety and tension symptoms in the gastrointestinal tract, treating abdominal pain, or treating gastrointestinal spasms secondary to organic diseases of the gastrointestinal system, e.g., gastroduodenal ulcers, acute enteritis, etc.

[0047] In some embodiments, the disclosure relates to an FDC comprising chlordiazepoxide, drotaverine, and one or more pharma- ceutically acceptable excipients, the FDC comprising a core having one or more layers and a coating surrounding the core, the coating comprising a gelatin shell or a non-gelatin-based material, such as HPMC or a plant material.

[0048] In some embodiments, the coating comprises polyvinylpyrrolidone (PVP), methylcellulose, ethylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose, dextrin, maltodextrin, lactose, D-mannitol, polyvinyl alcohol polymers, methacrylic acid copolymers, aminoalkyl methacrylate copolymers, or ethyl acrylate-methyl methacrylate copolymers, or combinations thereof.

[0049] In some embodiments, the coating comprises a plasticizer (e.g., triacetin, diethyl phthalate, etc.), an anti-adhesive agent (e.g., talc), an opacifier (e.g., titanium dioxide or aluminum oxide), or a colorant (e.g., natural and synthetic colors approved for pharmaceutical use), or a combination thereof.

[0050] In some embodiments, the film-coated formulations include one or more film-coating bases including polyvinyl alcohol or sodium carboxymethylcellulose, or methacrylic acid copolymers, or combinations thereof. Certain of these embodiments show improved storage stability for both the drotaverine and chlordiazepoxide active agents.

[0051] In some embodiments, the solvent system used for film coating comprises an aqueous solvent. In some embodiments, the solvent system comprises an aqueous alcoholic solvent. In some embodiments, the solvent system comprises a non-aqueous solvent comprising methylene chloride, acetone, or isopropyl alcohol, or a combination thereof.

[0052] In some embodiments, the disclosed FDCs use packaging forms that inhibit moisture penetration. Examples of such suitable packaging materials include a high-density polyethylene (HDPE) bulk dosage unit container. In some embodiments, the container may also include a desiccant. A desiccant is a drying agent that removes moisture from the air. Specific exemplary desiccants include silica gel, clay desiccants, calcium sulfate, calcium chloride, calcium oxide, zeolites, activated alumina, activated carbon, and combinations thereof.

[0053] In some embodiments, the disclosed FDCs of drotaverine and chlordiazepoxide are packaged in unit dose packages that are substantially impermeable to gas exchange, such as aluminum / aluminum (Alu / Alu) blisters, Alu-polychloro-3-fluoroethylene stringpolymer / PVC laminate blisters, etc.

[0054] In some embodiments of the present disclosure, the FDCs exhibit good chemical stability over the shelf life of the formulation and meet the standards desired by global regulatory agencies. In some embodiments, the FDCs are formulated into dosage forms, such as rapid release, immediate-release, slow-release, sublingual, intravenous, controlled release, delayed release, combination immediate and controlled release, nanoencapsulated formulations, and / or tamper-proof or abuse-proof delivery systems.

[0055] In some embodiments, the FDC disclosed herein comprises a benzodiazepine. Benzodiazepines are anxiolytic drugs used to treat anxiety disorders. In some embodiments, the anxiolytic drug is a benzodiazepine. Exemplary benzodiazepines include clonazepam, alprazolam, diazepam, oxazepam, lorazepam, or chlordiazepoxide, or combinations thereof.

[0056] Initial laboratory studies by the inventors showed that chlordiazepoxide API exhibited significant degradation in acidic environments as well as basic and oxidizing conditions. Drotaverine HCl showed the highest chemical stability in acidic pH, but degraded significantly in basic and peroxide solutions. Therefore, the inventors undertook a drug interaction study to evaluate the chemical stability of the samples. It was observed that mixing chlordiazepoxide and drotaverine HCl APIs resulted in significant chemical interactions between the two active ingredients. Mixing chlordiazepoxide and drotaverine resulted in their significant degradation. Mixing or blending the active agents drotaverine and chlordiazepoxide resulted in chemical interactions, thereby resulting in the degradation of the active moieties and the formation of therapeutically ineffective degradants as shown in Table 1 below. The presence of significant amounts of impurities indicated that mixing drotaverine and chlordiazepoxide resulted in their mutual degradation. [Table 1]

[0057] In some embodiments, the present disclosure provides a stable fixed dose combination (FDC) that provides drotaverine and chlordiazepoxide in one tablet for ease of administration and better patient compliance. In some embodiments, the FDC is an immediate release dosage form of drotaverine and chlordiazepoxide that provides equivalent or similar performance to the stand-alone commercial products of drotaverine and chlordiazepoxide tablets. In some embodiments, the FDC also exhibits one or more of sustained release, controlled release, and immediate release dissolution profiles. In some embodiments, the present disclosure provides a monolayer core or a monolayer core drug release system. For example, in some embodiments, the FDC is formulated as a monolayer core with a coating or an immediate release capsule. In some embodiments, the present disclosure provides "multilayer" or "multicomponent" dosage form units. In some embodiments, the dosage form is a "tablet-in-tablet" or "compression coated tablet", "tablet-in-capsule", "multi-layer tablet", "drug coated pellet", or "minitablets filled in a capsule". For example, in some embodiments, the FDC is formulated as a bi-layer or multi-layer core with a coating. In some embodiments, the present disclosure provides chemically stable FDCs of drotaverine and chlordiazepoxide to minimize significant chemical interactions of these two drugs when mixed.

[0058] In some embodiments, the FDC is manufactured by direct compression, dry granulation, wet granulation, or fluidized bed processing techniques. In some embodiments, drotaverine and chlordiazepoxide or a pharma- ceutically acceptable salt thereof are physically separated from one another. In some embodiments, physical separation involves disposing a separating or barrier layer "sandwiched" between a layer containing drotaverine and a layer containing chlordiazepoxide. In some embodiments, drotaverine and chlordiazepoxide are separated by including one active in the core and the other active in the coating. In some embodiments, drotaverine and chlordiazepoxide are separated by including the actives in granulation or pellets, containing one of the actives. In some embodiments, coating one or more of the API-containing compositions is employed, and the dosage form may then be formulated as a tablet or capsule.

[0059] In some embodiments, the present disclosure addresses the problem of instability due to chemical interactions between drotaverine and chlordiazepoxide or their pharma- ceutically acceptable salts, with at least one acidic component or antioxidant of the FDC, by means of a novel formulation design. In some embodiments, physical separation involves placing a separating or barrier layer "sandwiched" between a layer containing drotaverine and a layer containing chlordiazepoxide. In some embodiments, drotaverine and chlordiazepoxide are separated by including one active in the core and the other active in the coating. In some embodiments, drotaverine and chlordiazepoxide are separated by including the actives in a granule or pellet that contains one of the actives. In some embodiments, coating one or more of the API-containing compositions is employed, and the dosage form may then be formulated as a tablet or capsule.

[0060] In some embodiments, the FDCs are prepared by direct compression, which involves mixing drotaverine with pharma- ceutically acceptable excipients in a core and coating the core with a coating comprising chlordiazepoxide, with or without an inert polymer layer between the core and the coating of chlordiazepoxide. In some embodiments, the steps involved in the direct compression process are as follows:

[0061] The intragranular ingredients, including the active agent, diluent, disintegrant, and lubricant of the formulation, are weighed and mixed to obtain a final blend. The final blend is loaded into a tablet press, followed by compression to form the cores. The compressed cores are then coated using a suitable film coating composition until the weight of the coating is 1-5% of the weight of the FDC.

[0062] In some embodiments, the FDC is prepared by dry granulating drotaverine with pharma- ceutically acceptable excipients in a core, and chlordiazepoxide is coated onto the drotaverine-containing core, with or without an inert polymer layer between the core and the chlordiazepoxide coating. In some embodiments, the steps involved in the dry granulation process are as follows:

[0063] Weighing and blending of the intragranular components of the formulation is performed; followed by slugging or compression of the blended components to obtain tablets. After compression, milling and sieving of the tablets is performed to obtain sieved granules. The sieved granules are then mixed with disintegrants and lubricants resulting in the formation of the final blend. The final blend is loaded into a tablet press followed by compression to form tablets. The compressed cores can be coated using a suitable film coating composition until the weight of the coating is 1-5% of the weight of the FDC.

[0064] In some embodiments, the FDC is prepared by wet granulation with drotaverine and pharma- ceutically acceptable excipients in the core, and chlordiazepoxide is coated onto the drotaverine-containing core with or without an inert polymer layer between the drotaverine core and the chlordiazepoxide coating. In some embodiments, the steps involved in the wet granulation process are as follows:

[0065] Weighing and mixing of the intragranular ingredients of the formulation to obtain the blended granules is carried out by high shear granulation with binder solution using a Rapid Mixer Granulator (SARAL Engineering, Gujarat, India). Blending is followed by drying to obtain the dry granules. The dry granules are then mixed with disintegrants and lubricants to give the final blend for the cores. The final blend is loaded into a tablet press followed by compression to obtain the compressed tablets. The compressed tablets may be coated using a suitable film coating composition until the weight of the coating is 1-5% of the weight of the FDC.

[0066] In some embodiments, the FDC is prepared by fluid bed processing which involves preparing granules of drotaverine in a core with pharma- ceutically acceptable excipients, and chlordiazepoxide is coated onto the core with or without an inactive layer between the core and the chlordiazepoxide coating. In some embodiments, the steps involved in the fluid bed processing process are as follows:

[0067] After weighing and mixing the intragranular components of the formulation, this is followed by forming granules from the mixed intragranular components and binder solution by fluid bed granulation; followed by drying of the granules to obtain dry granules. The dry granules are then mixed with a disintegrant and a lubricant resulting in the formation of a final blend. The final blend is loaded into a tablet press and compressed to form cores. The compressed cores may be coated using a suitable film coating composition until the weight of the coat is 1-5% of the weight of the FDC.

[0068] In some embodiments, the FDC is prepared by direct compression, which involves preparing individual core layers, a layer comprising chlordiazepoxide and pharma- ceutically acceptable excipients and another layer comprising drotaverine and pharma- ceutically acceptable excipients. In some embodiments, the blend of individual layers is then compressed to form a bilayer core. In some embodiments, a trilayer core is formed by including an inert excipient layer sandwiched between a drotaverine layer and a chlordiazepoxide layer. In some embodiments, the inert excipient comprises mannitol, dicalcium phosphate, anhydrous lactose, colloidal silicon dioxide, starch (dried), magnesium stearate, or purified talc. In some embodiments, the steps involved in the direct compression process are as follows:

[0069] For each layer, the intragranular components of the formulation, including active agent, diluent, disintegrant, and lubricant, are weighed and mixed separately to obtain separate final blends for the individual layers of the bilayer core. The final blends of the two layers are loaded into separate hoppers of a tablet press and compressed to obtain the compressed bilayer core. The compressed bilayer core may be coated using a suitable film coating composition until the weight of the coat is 1-5% of the weight of the FDC.

[0070] In some embodiments, the FDC is prepared by dry granulation, which includes preparing individual core layers, a core layer comprising chlordiazepoxide and pharma- ceutically acceptable excipients, and another layer comprising drotaverine and pharma- ceutically acceptable excipients. In some embodiments, the individual layers are then compressed to form a bilayer core. In some embodiments, a trilayer core is formed by including an inert excipient layer sandwiched between a drotaverine layer and a chlordiazepoxide layer. In some embodiments, the inert excipient comprises mannitol, dicalcium phosphate, anhydrous lactose, colloidal silicon dioxide, starch (dried), magnesium stearate, or purified talc. In some embodiments, the manufacturing steps involved in the dry granulation process are as follows:

[0071] After weighing and mixing the intragranular components of the formulation to obtain the blended components for each layer of the core separately; slugging or compression of the separate blended components follows to obtain the compacts for each layer of the core. After compression, milling and sieving of the separate compacts is performed for each layer of the core. The separate sieved granules are then mixed with a disintegrant and a lubricant, resulting in the formation of the final blend of the two separate layers. The final blend of each separate layer is loaded into separate hoppers of a tablet press, followed by compression to form the compressed bilayer core. The compressed bilayer core can be coated using a suitable film coating composition until the weight of the coating is 1-5% of the weight of the FDC.

[0072] In some embodiments, the FDC is prepared by wet granulation, which includes preparing individual core layers, a layer comprising chlordiazepoxide and pharma- ceutically acceptable excipients and another layer comprising drotaverine and pharma- ceutically acceptable excipients. In some embodiments, the individual layers are then compressed to form a bilayer core. In some embodiments, a trilayer core is obtained by including an inert excipient layer sandwiched between a drotaverine layer and a chlordiazepoxide layer. In some embodiments, the inert excipient comprises mannitol, dicalcium phosphate, anhydrous lactose, colloidal silicon dioxide, starch (dried), magnesium stearate, or purified talc. In some embodiments, the steps involved in the wet granulation process are as follows:

[0073] The intragranular components of the formulation for each layer of the core are weighed and mixed separately, and the mixed intragranular components are sheared with a binder solution to obtain mixed granules for each layer of the core by high shear granulation using a rapid mixer granulator (SARAL Engineering, Gujarat, India). The separate granules are then dried to obtain dry granules for each layer of the core. The separate dry granules are then mixed with a disintegrant and a lubricant to result in separate final blends for the individual layers. The separate final blends for the separate layers are loaded into separate hoppers of a tablet press followed by compression to obtain the compressed bilayer core. The compressed tablets may be coated using a suitable film coating composition until the weight of the coating is 1-5% of the weight of the FDC.

[0074] In some embodiments, the FDC is prepared by fluidized bed processing to prepare individual core layers, a layer containing chlordiazepoxide and pharma- ceutically acceptable excipients and another layer containing drotaverine and pharma- ceutically acceptable excipients. In some embodiments, the individual layers are then compressed to form a bilayer core. In some embodiments, a trilayer core is obtained by including an inert excipient layer sandwiched between a drotaverine layer and a chlordiazepoxide layer. In some embodiments, the inert excipient comprises mannitol, dicalcium phosphate, anhydrous lactose, colloidal silicon dioxide, starch (dried), magnesium stearate, or purified talc. In certain embodiments, the steps involved in the fluidized bed processing process are as follows:

[0075] After weighing and mixing the intragranular components of the formulation for each layer of the core, the formation of granules for each layer of the core from the mixed intragranular components and binder solution is followed by fluid bed granulation. The separate granules are then dried to obtain dry granules for each layer of the core. The separate dry granules are then mixed with a disintegrant and a lubricant resulting in the formation of separate final blends for the individual layers. The separate final blends for the separate layers are loaded into separate hoppers of a tablet press followed by compression to obtain a bilayer core. The compressed tablets may be coated using a suitable film coating composition until the weight of the coating is 1-5% of the weight of the FDC.

[0076] In some embodiments, the FDC is prepared using more than one process. In some embodiments, one process is used to prepare one layer of the FDC and a different process is used to prepare a second layer of the FDC. For example, the layer containing drotaverine or a pharma- ceutically acceptable salt thereof is prepared using a direct compression process, a dry granulation process, a wet granulation process, or a fluidized bed process, and the second layer containing the benzodiazepine is prepared using one of the other three processes. For example, the layer containing drotaverine or a pharma- ceutically acceptable salt thereof is prepared using a wet granulation process, and the second layer containing the benzodiazepine is prepared using a direct compression process.

[0077] In some embodiments, the granulation liquid may include an aqueous or non-aqueous solvent along with other excipients such as a diluent or filler, binder, surfactant, antioxidant, acidifier, disintegrant, glidant, or lubricant, or combinations thereof.

[0078] In some embodiments, diluents used in the present disclosure include sugars such as lactose monohydrate, lactose anhydrous, mannitol, starches such as corn starch, corn starch, pregelatinized starch, and starch 1500, cellulose derivatives such as microcrystalline cellulose and powdered cellulose and directly compressible grades of cellulose, etc. In some embodiments, diluents include sorbitol, xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, or tribasic calcium phosphate, or combinations thereof.

[0079] In some embodiments, disintegrants used in the present disclosure include dry starch, sodium starch glycolate, risperidone, croscarmellose sodium, L-HPC, or alginic acid, or combinations thereof.

[0080] In some embodiments, binders used in the present disclosure include hydroxypropyl cellulose (also called HPC) (e.g., Klucel™ LF and Klucel™ EXF), various grades of hydroxypropyl methylcellulose (also called hypromellose) (e.g., Methocel™ products), various grades of polyvinylpyrrolidone or povidone (e.g., grades K25, K29, K30, and K90, etc.), copovidone (e.g., Plasdone™ S 630), powdered acacia, gelatin, guar gum, carbomer (e.g., Carbopol® products), methylcellulose, polymethacrylate, or starch, or combinations thereof.

[0081] In some embodiments, surfactants used in the present disclosure include polyoxyethylene-polyoxypropylene block copolymers (poloxamers), alkyl sulfates (e.g., sodium lauryl sulfate, sodium stearyl sulfate, sodium oleyl sulfate, and sodium cetyl sulfate), alkylaryl sulfonates (e.g., sodium dodecylbenzenesulfonate and sodium dialkylsulfosuccinate), polyethylene glycols, or polysorbates, or combinations thereof.

[0082] In some embodiments, lubricants used in this disclosure include magnesium stearate, glyceryl monostearate, palmitic acid, talc, carnauba wax, calcium stearate, sodium stearate, sodium lauryl sulfate, magnesium lauryl sulfate, zinc stearate, polyoxymethylene monostearate, calcium silicate, silicon dioxide, hydrogenated vegetable fats and oils, stearic acid, or glyceryl behenate, or combinations thereof.

[0083] In some embodiments, glidants for use in this disclosure include colloidal silicon dioxide and / or talc.

[0084] In some embodiments, the tablet dosage form is film coated to mask the bitter taste of drotaverine when swallowed by the patient. In some embodiments, film coating the tablets also improved the storage stability of the formulation for both drotaverine and chlordiazepoxide active agents. EXAMPLES

[0085] Without limiting the scope of the present disclosure, some examples are described below for representative purposes.

[0086] Example 1: Drotaverine and chlordiazepoxide tablets (drotaverine in the tablet core with chlordiazepoxide in the coating) Tablets are manufactured containing drotaverine in the core and chlordiazepoxide in the film coating. The tablets are formulated by a wet granulation process. The process involves blending the intragranular ingredients in the core, including granules of drotaverine (approximately 25-40% w / w), along with pharma- ceutically acceptable excipients. The granules are dried and then blended with a disintegrant and lubricant to form a final blend. The final blend is then loaded into a tablet press and compressed to form compressed cores. The compressed cores are coated using a suitable film coating composition. The core coating contains chlordiazepoxide (0.5-3.00% w / w) with or without an inert polymer coating between the core and the chlordiazepoxide coating layer.

[0087] The % w / w of active substances and pharma- ceutically acceptable excipients of the tablets are set forth in Table 2 below: [Table 2]

[0088] Example 2: Drotaverine and Chlordiazepoxide Tablets (Drotaverine and Chlordiazepoxide in the Tablet Core) Tablets are manufactured that contain drotaverine and chlordiazepoxide in the core and further contain a film coating. The tablets are formulated by a wet granulation process. The process involves blending intragranular ingredients in the core, including granules of drotaverine (about 25-40% w / w) and chlordiazepoxide (about 0.5-3.5% w / w), along with pharma- ceutically acceptable excipients. The granulation process, and the excipients used therein, stabilize the drotaverine HCl and chlordiazepoxide HCl in the tablet. The granules are dried and then blended with a disintegrant and a lubricant to form a final blend. The final blend is then loaded into a tablet press and compressed to form compressed cores. The compressed cores are coated using a suitable film coating composition.

[0089] The % w / w of active substances and pharma- ceutically acceptable excipients in the tablets are set forth in Table 3 below: [Table 3]

[0090] Example 3: Drotaverine and Chlordiazepoxide bilayer tablets (wet granulation process) A bilayer tablet is manufactured containing drotaverine and chlordiazepoxide in separate layers. The tablets are formulated by wet granulation.

[0091] This process of preparing bilayer tablets containing drotaverine and chlordiazepoxide in separate layers involves mixing the active substances drotaverine (about 30-50% w / w) and chlordiazepoxide (about 2-7% w / w) and intragranular ingredients separately to obtain a mixed granule by high shear granulation by using a rapid mixer granulator. The mixed granule is then subjected to drying to obtain a dry granule. The dry granule is then mixed with a disintegrant and a lubricant resulting in the formation of a final blend for the drotaverine layer and a final blend for the chlordiazepoxide layer. The separate layers are loaded into separate hoppers of a tablet press followed by compression of the separate layers to obtain a compressed bilayer core. The compressed bilayer core is then coated using a suitable film coating composition.

[0092] The % w / w of active substances and pharma- ceutically acceptable excipients in the tablets are set forth in Tables 4-7 below: [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11]

[0093] Example 4: Drotaverine and Chlordiazepoxide bilayer tablets (two different processes) Bilayer tablets are manufactured containing drotaverine and chlordiazepoxide in separate layers in the core: the drotaverine layer is prepared using a wet granulation method and the chlordiazepoxide layer is prepared using a direct compression method.

[0094] The process of preparing the drotaverine layer involves mixing drotaverine (about 30-50% w / w) and intragranular ingredients to obtain mixed granules by high shear granulation with a binder solution using a rapid mixer granulator. The mixed granules are then subjected to drying to obtain dry granules. The dry granules are then mixed with a disintegrant and a lubricant resulting in the formation of the final blend for the drotaverine layer.

[0095] The process of preparing the chlordiazepoxide layer involves mixing chlordiazepoxide (about 2-7% w / w) and the intragranular ingredients to obtain a final blend that is loaded into a tablet press followed by compression to form the layer.

[0096] The drotaverine layer and the chlordiazepoxide layer are loaded into separate hoppers of a tablet press, followed by compression of the separate layers to obtain a compressed bilayer core, which is then coated using a suitable film coating composition.

[0097] The % (w / w) of active substance and pharma- ceutically acceptable excipients in the tablets are set forth in Table 8 below: [Table 12]

[0098] Example 5: Drotaverine and Chlordiazepoxide double layer tablets (dry granulation process) A bilayer tablet is manufactured containing drotaverine and chlordiazepoxide in separate layers. The tablets are formulated by dry granulation.

[0099] The process for producing bilayer tablets containing drotaverine and chlordiazepoxide in separate layers involves separately blending the active substances drotaverine (about 30-50% w / w) and chlordiazepoxide (about 2-7% w / w) and the granular components of each layer to obtain separate blended components for each layer of the core, followed by slugging or compression of the separate blended components to obtain compacts for each layer of the core. After compression, the compacts are milled and sieved to obtain separate sieved granules for each layer of the core. The separate sieved granules are then mixed with a disintegrant and a glidant, resulting in the formation of a final blend of the two separate layers. The final blends of each individual layer are loaded into separate hoppers of a tablet press, followed by compression to form a compressed bilayer core. The compressed bilayer cores can be coated using a suitable film coating composition until the weight of the coating is 1-5% of the weight of the FDC.

[0100] The % w / w of active substances and pharma- ceutically acceptable excipients in the tablets are set forth in Tables 9-11 below: [Table 13] [Table 14] [Table 15]

[0101] Example 4: Stability Data The particular FDCs described above have undergone stability testing. The FDCs have demonstrated good chemical stability as per currently available accelerated stability data using ICH guidelines (40°C ± 2°C / 75% RH ± 5% RH for 6 months). Stability data for exemplary monolayer and bilayer tablets of the FDCs of the present disclosure are shown in Tables 12 and 13 below. [Table 16] [Table 17]

[0102] Although the subject matter has been described herein with reference to certain embodiments, other embodiments are possible. For illustrative purposes, the disclosed combinations and formulations include drotaverine and chlordiazepoxide as anticonvulsants and anxiolytics, respectively. However, those skilled in the art will understand that the scope of the disclosure extends to other combinations and formulations of anticonvulsants and anxiolytics known in the art.

Claims

1. A fixed dose combination comprising drotaverine or a pharma- ceutically acceptable salt thereof and at least one benzodiazepine.

2. 2. The fixed dose combination of claim 1, wherein the at least one benzodiazepine is chlordiazepoxide or a pharma- ceutically acceptable salt thereof.

3. 3. The fixed dose combination of claim 1 or 2, wherein the fixed dose combination comprises a core, the core comprising at least one layer.

4. The fixed dose combination of any one of claims 1 to 3, wherein the fixed dose combination comprises a coating surrounding a core.

5. 5. The fixed dose combination of claim 4, wherein the core comprises one layer, the core comprising drotaverine or a pharma- ceutically acceptable salt thereof, and chlordiazepoxide or a pharma- ceutically acceptable salt thereof.

6. 5. The fixed dose combination of claim 4, wherein the core comprises drotaverine or a pharma- ceutically acceptable salt thereof and the coating surrounding the core comprises chlordiazepoxide or a pharma- ceutically acceptable salt thereof.

7. 5. The fixed dose combination of claim 4, wherein the core comprises at least two layers, the first layer comprising drotaverine or a pharma- ceutically acceptable salt thereof and the second layer comprising chlordiazepoxide or a pharma- ceutically acceptable salt thereof.

8. 8. The fixed dose combination of claim 7, wherein the core further comprises a third layer, the third layer being between the first layer comprising drotaverine or a pharma- ceutically acceptable salt thereof and the second layer comprising chlordiazepoxide or a pharma- ceutically acceptable salt thereof, the third layer comprising an inert excipient.

9. 9. The fixed dose combination of claim 1, wherein the fixed dose combination comprises 20-300 mg of drotaverine or a pharma- ceutically acceptable salt thereof.

10. 10. The fixed dose combination of claim 1, wherein the fixed dose combination comprises a pharma- ceutically acceptable salt of drotaverine, the pharma- ceutically acceptable salt of drotaverine being drotaverine hydrochloride.

11. 11. The fixed dose combination of any one of claims 1 to 10, comprising 2.5 to 40 mg of chlordiazepoxide or a pharma- ceutically acceptable salt thereof.

12. 12. The fixed dose combination of any one of claims 1 to 11, wherein the fixed dose combination comprises a pharma- ceutically acceptable salt of chlordiazepoxide, wherein the pharma- ceutically acceptable salt of chlordiazepoxide is chlordiazepoxide hydrochloride.

13. 13. The fixed dose combination of any one of claims 1 to 12, wherein the coating further comprises a coating agent, the coating agent comprising polyvinylpyrrolidone, methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, dextrin, maltodextrin, lactose, D-mannitol, polyvinyl alcohol polymers, methacrylic acid copolymers, aminoalkyl methacrylate copolymers, or ethyl acrylate-methyl methacrylate copolymers, or combinations thereof.

14. 14. The fixed dose combination of claim 13, wherein the coating further comprises a plasticizer, an anti-blocking agent, an opacifier, a colorant, or a combination thereof.

15. 15. The fixed dose combination of any one of claims 1 to 14, further comprising an acidifier, an antioxidant, a diluent, a binder, a surfactant, a lubricant, or a glidant, or a combination thereof.

16. 16. The fixed dose combination of any one of claims 1 to 15, wherein the acidifying agent comprises citric acid, fumaric acid, lactic acid, maleic acid, malic acid or tartaric acid, or a combination thereof.

17. 17. The fixed dose combination of any one of claims 1 to 16, wherein the fixed dose combination comprises an antioxidant, the antioxidant comprising butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, sodium thiosulfate, propyl gallate, ascorbic acid, or cysteine, or a combination thereof.

18. 18. The fixed dose combination of any one of claims 1 to 17, wherein the fixed dose combination comprises a diluent, the diluent comprising lactose monohydrate, lactose anhydrous, mannitol, corn starch, corn starch, pregelatinized starch, starch 1500, microcrystalline cellulose, powdered cellulose, directly compressible grades of cellulose, sorbitol, xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, or tribasic calcium phosphate, or a combination thereof.

19. 19. The fixed dose combination of any one of claims 1 to 18, wherein the fixed dose combination comprises a binder, the binder comprising hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, copovidone, powdered acacia, gelatin, guar gum, carbomer, methylcellulose, polymethacrylate, or starch, or a combination thereof.

20. 20. The fixed dose combination of any one of claims 1 to 19, wherein the fixed dose combination comprises a surfactant, the surfactant comprising a polyoxyethylene-polyoxypropylene block copolymer, an alkyl sulfate, an alkylaryl sulfonate, a polyethylene glycol, or a polysorbate, or a combination thereof.

21. 21. The fixed dose combination of any one of claims 1 to 20, wherein the fixed dose combination comprises a lubricant, the lubricant comprising magnesium stearate, glyceryl monostearate, palmitic acid, talc, carnauba wax, calcium stearate, sodium stearate, sodium lauryl sulfate, magnesium lauryl sulfate, zinc stearate, polyoxymethylene monostearate, calcium silicate, silicon dioxide, hydrogenated vegetable fats and oils, stearic acid, or glyceryl behenate, or a combination thereof.

22. 22. The fixed dose combination of any one of claims 1 to 21, wherein the fixed dose combination comprises a glidant, the glidant comprising colloidal silicon dioxide or talc, or a combination thereof.

23. The fixed dose combination according to any one of claims 1 to 22, wherein the fixed dose combination is prepared using a direct compression process.

24. The fixed dose combination according to any one of claims 1 to 22, wherein the fixed dose combination is prepared using a dry granulation process.

25. The fixed dose combination according to any one of claims 1 to 22, wherein the fixed dose combination is prepared using a wet granulation process.

26. 23. The fixed dose combination according to any one of claims 1 to 22, wherein the fixed dose combination is prepared using a fluid bed process.

27. 27. The fixed dose combination of any one of claims 1 to 26, wherein the fixed dose combination is packaged with a pharma- ceutically acceptable desiccant.

28. The fixed dose combination of any one of claims 1 to 27, wherein the fixed dose combination is packaged in an inert gas environment.

29. A fixed dose combination comprising drotaverine hydrochloride, chlordiazepoxide, and citric acid, the formulation comprising a bilayer core having a coating, the drotaverine hydrochloride being in a first layer of the core and the chlordiazepoxide being in a second layer of the core.

30. 30. The fixed dose combination of claim 29, wherein the fixed dose combination is prepared using a dry granulation process.

31. A method for preparing a fixed dose combination of drotaverine or a pharma- ceutically acceptable salt thereof and chlordiazepoxide or a pharma- ceutically acceptable salt thereof, comprising a core having a coating using a direct compression process, the method comprising: a. Mixing the intragranular ingredients for the fixed dose combination core; b. Loading the intragranular ingredients into a tablet press; c. compressing the intragranular ingredient mixture to form a fixed dose combination core; and d. Coating the core with a film until the weight of the film is 1-5% of the weight of the fixed dose formulation; A method comprising:

32. A method for preparing a fixed dose combination of drotaverine or a pharma- ceutically acceptable salt thereof and chlordiazepoxide or a pharma- ceutically acceptable salt thereof, comprising a core having a coating using a dry granulation process, said method comprising: a. Mixing the intragranular ingredients for the fixed dose combination core; b. slugging or compressing the intragranular component mixture to obtain a compact; c. milling and sieving the compact to obtain sieved granules; d. mixing the sieved granules with at least one excipient to obtain a final blend; e. Loading the final blend into a tablet press; f. compressing the final blend to form a fixed dose combination core; and g. Coating the core with a coating until the weight of the coating is 1-5% of the weight of the fixed dose formulation; A method comprising:

33. A method for preparing a fixed dose combination of drotaverine or a pharma- ceutically acceptable salt thereof and chlordiazepoxide or a pharma- ceutically acceptable salt thereof, comprising a core having a coating using a wet granulation process, said method comprising: a. Mixing the intragranular ingredients for the fixed dose combination core; b. shearing the intragranular ingredient mixture with a binder solution using a rapid mixer granulator to obtain granules; c. drying the granules to obtain dry granules; d. mixing the dry granules with at least one excipient to obtain a final blend; e. Loading the final blend into a tablet press; f. compressing the final blend to form tablet cores; and g. Coating the core with a coating until the weight of the coating is 1-5% of the weight of the fixed dose formulation; A method comprising:

34. A method for preparing a fixed dose combination of drotaverine or a pharma- ceutically acceptable salt thereof and chlordiazepoxide or a pharma- ceutically acceptable salt thereof, comprising a core having a coating using a fluidized bed process, said method comprising: a. Mixing the intragranular ingredients for the fixed dose combination core; b. forming granules from the mixed intragranular ingredients and binder solution by fluid bed granulation; c. drying the granules to obtain dry granules; d. mixing the dry granules with at least one excipient to obtain a final blend; e. Loading the final blend into a tablet press; f. compressing the final blend to form a fixed dose combination core; and g. Coating the core with a coating until the weight of the coating is 1-5% of the weight of the fixed dose formulation; Including: Method.

35. A method for preparing a fixed dose combination of drotaverine or a pharma- ceutically acceptable salt thereof and chlordiazepoxide or a pharma- ceutically acceptable salt thereof, comprising a multi-layer core having a coating using a direct compression process, the method comprising: a. mixing the intragranular ingredients for each layer of the core separately; b. Loading a separate final blend for each layer of the core into a tablet press; c. compressing the separate final blends to form a multi-layered core of a fixed dose combination; and d. Coating the core with a film until the weight of the film is 1-5% of the weight of the fixed dose formulation; A method comprising:

36. A method for preparing a fixed dose combination of drotaverine or a pharma- ceutically acceptable salt thereof and chlordiazepoxide or a pharma- ceutically acceptable salt thereof, comprising a multi-layered core having a coating using a dry granulation process, said method comprising: a. mixing the intragranular ingredients for each layer of the core separately; b. slugging or compressing the separate intragranular component mixtures to obtain compacts for each layer of the core; c. milling and sieving the separate compacts to obtain separate sieved granules for each layer of the core; d. mixing the separate sieved granules with at least one excipient to obtain a final blend for each layer of the core; e. Loading a separate final blend for each layer of the core into a tablet press; f. compressing the separate final blends to form a multi-layered fixed dose combination core; and g. Coating the core with a coating until the weight of the coating is 1-5% of the weight of the fixed dose formulation; A method comprising:

37. A method for preparing a fixed dose combination of drotaverine or a pharma- ceutically acceptable salt thereof and chlordiazepoxide or a pharma- ceutically acceptable salt thereof, comprising a multi-layered core having a coating using a wet granulation process, said method comprising: a. mixing separately the intragranular ingredients for each layer of the multi-layer core; b. Shearing the separate intragranular component mixtures with a binder solution using a rapid mixer granulator to obtain granules for each layer of the core; c. drying the separate granules to obtain a dry granule for each layer of the core; d. Mixing the separate dry granules with at least one excipient to obtain a final blend for each layer of the core; e. Loading a separate final blend for each layer of the core into a tablet press; f. compressing the final blend to form a multi-layered fixed dose combination core; and g. Coating the core with a coating until the weight of the coating is 1-5% of the weight of the fixed dose formulation; A method comprising:

38. A method for preparing a fixed dose combination of drotaverine or a pharma- ceutically acceptable salt thereof and chlordiazepoxide or a pharma- ceutically acceptable salt thereof, comprising a multi-layer core having a coating using a fluidized bed process, said method comprising: a. mixing the intragranular ingredients for each layer of the core separately; b. For each layer of the core, forming granules from the mixed intragranular ingredients and binder solution by fluid bed granulation: c. drying the separate granules to obtain a dry granule for each layer of the core; d. Mixing the separate dry granules with at least one excipient to obtain a final blend for each layer of the core; e. Loading a separate final blend for each layer of the core into a tablet press; f. compressing the final blend to form a multi-layered fixed dose combination core; and g. Coating the core with a coating until the weight of the coating is 1-5% of the weight of the fixed dose formulation; A method comprising:

39. 31. A method for treating at least one symptom of a gastrointestinal disorder characterized by a spastic state of smooth muscle in a subject in need thereof, comprising administering to the subject a formulation according to any one of claims 1 to 30.

40. 40. The method of claim 39, wherein the disorder comprises irritable bowel syndrome, symptoms of gastrointestinal anxiety and tension in the gastrointestinal tract, abdominal pain, or gastrointestinal spasms secondary to an organic disease of the digestive system, or a combination thereof.

41. 31. A pharmaceutical composition for use in the treatment of at least one symptom of a gastrointestinal disorder characterized by a spastic state of smooth muscle in a subject in need thereof, comprising administering to the subject a formulation according to any one of claims 1 to 30.

42. 42. The pharmaceutical composition for use according to claim 41, wherein the disorder comprises irritable bowel syndrome, symptoms of gastrointestinal anxiety and tension in the gastrointestinal tract, abdominal pain, or gastrointestinal spasms secondary to organic diseases of the digestive system, or combinations thereof.

43. A combination comprising drotaverine or a pharma- ceutically acceptable salt thereof and at least one benzodiazepine formulated as a single medicament.

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