Stable pharmaceutical oral liquid formulations of anti-spasmodic agents

Abstract

The present disclosure provides oral suspension formulations of drotaverine or a salt thereof, methods for their preparation, and their use in therapy.

Description

Technical Field

[0001] The present disclosure relates to stable pharmaceutical oral suspension formulations of anticonvulsants. More specifically, the present disclosure relates to stable pharmaceutical oral suspension formulations of drotaverine or its salts. The present disclosure also relates to methods for preparing such formulations and their uses. Background Art

[0002] Oral administration route of medicine is preferred in pediatric patients.Different from oral solid dosage forms (such as tablets or capsules) being acceptable adults for most patients, pediatric patients including neonates (infants within 28 days after birth), newborns, toddlers and young children cannot swallow conventional tablets.They prefer medicines of very small volume dosages to avoid volume overload.Therefore, oral suspension dosage forms, such as suspension dosage forms used in drop form are considered to be suitable preparations for infants and very young children.Drops from suspension provide delivery of small volume, delivery of low-dose drugs, be easy to swallow and use flexibility.

[0003] The development of age-appropriate medicines for infants and children involves not only understanding their preferences for different formulations, flavors, and product textures, but also understanding the physical and biochemical differences between children and adults. The design of pediatric formulations can take into account factors such as ensuring minimal impact on the child's lifestyle, administering a low dose frequency, providing a palatable dosage form, allowing for personalized dosing or dose fractionation for effective treatment, providing adequate bioavailability, avoiding toxic excipients, providing a convenient and reliable route of administration, and using a robust manufacturing process at minimal cost.

[0004] Taste is an important and key parameter in the administration of oral preparations. Infants are born with a sensitive sense of taste, and may even have taste buds that are more widely distributed than adults. Newborns can distinguish sweetness and bitterness with the taste buds of tonsils, throat and back of the tongue. Newborns usually prefer sweetness, such as breast milk. Various evidences show that the liking of sweetness is innate (TR Maone et al., A New Method for Delivering a Taste without Fluids to Preterm and Term Infant, 23 Dev., Psychobiol., 179 (1990)). Bitterness is considered to be opposite to sweetness, and is generally considered to be bad and undesirable. Many drugs are naturally bitter, and bitterness is one of the problems encountered during the development of drug formulations. The bitterness of drugs can cause patients (especially infants and children) to be unwilling or unable to swallow such preparations.

[0005] Simple taste masking is sometimes not enough to hide the bitter taste of the drug and requires more complex formulations. Excipients are often used to improve palatability, shelf life and / or improve the manufacturing process. Many excipients are known to be harmful to newborns, so the choice of excipients in neonatal drugs is another important factor that needs to be monitored. Although excipients are generally considered to be "inactive ingredients", many excipients that are pharmacologically inert in adults may be toxic to newborns and children. For example, the use of small amounts of ethanol as a solvent in preparations such as diazepam oral solution is not a problem for adults, but can cause CNS (central nervous system) depression in newborns, making it unsuitable for use in this population. In addition, the inclusion of propylene glycol in preparations used in newborns (e.g., cetirizine oral solution) has caused concerns about ototoxicity and CNS toxicity in the past (Linakis et al., 2016; Clinical Pharmacokinetics, Vol. 55, pp. 185–196). Therefore, certain excipients, such as ethanol, propylene glycol, benzyl alcohol, and parabens, can impede continued organ development in neonates and children and are not recommended. Excipients used to develop products must be safe and acceptable for use in neonates and children.

[0006] In infants and young children, abdominal pain is a common problem and may be a difficult-to-treat symptom. Although the causes of pain are diverse, abdominal pain occurs in newborns until adulthood. Separating this population by age groups of 0 to 1, 1 to 6, 6 to 11, and 11 to 18 years old helps diagnose and design appropriate preparations for the treatment of pain. Due to the wide age range of the pediatric population, a single preparation will be unlikely to be suitable for spanning an 18-year range, which may lead to multiple products. Although older children aged 6 to 11 or 11 to 18 years old can administer solid oral dosage forms, infants and children under 6 years old cannot easily swallow solid oral dosage forms. In their age group, liquid oral preparations can provide accurate dose titration that is easy to administer.

[0007] Drotaverine hydrochloride is a benzylisoquinoline derivative and an analog of papaverine. Its chemical name is 1-[(3,4-diethoxyphenyl)methylene]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline, and its molecular formula is C 24 H 31 NO4.HCl.

[0008] Drotaverine is an efficient spasmolytic that acts directly on smooth muscle and has no anticholinergic side effects. It is used to treat various gastrointestinal diseases, biliary dyskinesias and vasomotor diseases associated with smooth muscle spasms. Drotaverine adsorbs on the cell surface and changes the cell membrane potential and permeability. It has a dual mechanism of action by inhibiting the enzyme phosphodiesterase IV (PDE IV) and calmodulin (CAM), which is a calcium binding protein. This causes an increase in the level of cyclic adenosine monophosphate (cAMP) in smooth muscle, thereby reducing free calcium ions (Ca 2+ ) concentration. 2+ The decrease of ions and the inhibition of calmodulin lead to the formation of the calmodulin-calcium complex (CAM-Ca 2+ ) formation. This process inhibits myosin light chain kinase (MLCK), leading to dephosphorylation of actin phosphocomplexes and relaxation of smooth muscle.

[0009] Some pharmacokinetic parameters of drotaverine, such as elimination, half-life, plasma clearance, renal clearance and apparent distribution volume, may not be affected by the route of drug administration. The pharmacokinetic parameters of immediate release (IR) drotaverine tablets (80 mg) have been studied. [OO Bolaji et al., Pharmacokinetics and Bioavailability of Drotaverine in Humans, 21 Eur. J. Drug Metab. Pharmacokinet. 217 (1996)]. The drug is mainly eliminated by non-renal routes, as renal clearance accounts for only 0.31+ / -0.13% of the total plasma clearance. The absolute bioavailability is variable and subject-dependent, and ranges from 24.5% to 91%, with a mean of 58.2+ / -18.2% (mean+ / -SD). This indicates that the high variation in the bioavailability of drotaverine hydrochloride after oral administration leads to significant inter-individual differences in the therapeutic response to the drug. In pharmacokinetic and bioavailability studies, drotaverine has been shown to be rapidly absorbed, with onset of action within 12 minutes after oral administration of an 80 mg strength IR tablet. Peak plasma levels occur after 1 to 3 hours, while the elimination half-life is 7 to 11.95 hours. In toxicology studies, drotaverine was considered to be very safe, as the reported oral LD50 of drotaverine is greater than 1000 mg / Kg body weight, thus having a wide therapeutic index.

[0010] Currently, drotaverine is available as a conventional IR tablet in the strength of 40 mg and 80 mg tablets for the relief and prevention of smooth muscle spasms in various organs, regardless of their function and innervation. The approved daily dose of drotaverine tablets is 120 mg to 240 mg (2 to 3 divided doses) for adults, 80 mg to 200 mg (2 to 5 divided doses) for children aged 6 to 18 years, and 40 mg to 120 mg (2 to 3 divided doses) for children aged 1 to 6 years. In children, the oral suspension of drotaverine is also used to treat abdominal pain. It can be used in two different concentrations: 10 mg / 5 mL and 20 mg / 5 mL. The dose of drotaverine suspension is 0.5 mL / kg or 1 mL / kg body weight. TID up to 120 mg / day in children aged 1 to 6 years, and 0.5 mL / kg or 1 mL / kg body weight TID up to 200 mg / day in children aged 6 to 12 years. The strengths of drotaverine suspensions currently available on the market (10 mg / 5 mL or 20 mg / 5 mL) are not easily administered to infants and children under 3 years of age due to the large volume per unit dose. Therefore, there is a need to develop a suitable concentrated form of drotaverine formulation that can be easily administered in a reduced volume, preferably up to 1 mL in the form of an oral suspension or spray.

[0011] Drotaverine is highly effective alone or in combination in relieving painful cramps from a wide variety of gastrointestinal, urological, gynecological, and / or obstetric conditions and is the first choice emergency medication for the relief of abdominal pain.

[0012] Drotaverine suspension can be administered to treat acute abdominal pain in children. Children often have poor cognition of the onset of illness, location of pain, and cannot effectively describe or vocalize the character, severity, duration, or radiation of pain, which is very important for diagnosis. For example, a child may not be able to describe the type of pain caused by acute appendicitis, which is very common in children. As a PDE IV inhibitor, drotaverine can be used to selectively relieve muscle abdominal pain without masking other symptoms of acute abdominal pain. This feature of drotaverine makes it unique compared to other existing antispasmodic / anticholinergic drugs.

[0013] Drotaverine has been shown to reduce abdominal pain without the side effects associated with anticholinergics. It is an effective, safe agent for treating recurrent abdominal pain in childhood. It is most commonly considered for digestive tract problems in preschool and school-age children. Drotaverine is nontoxic, has minimal side effects, and can be administered to children without long-term problems.

[0014] Irritable bowel syndrome (IBS) is often associated with flatulence that causes pain and discomfort to the patient. In some embodiments, anti-flatulence active ingredients can be used to treat problematic conditions for gas retention, such as excessive air swallowing in infants, colic, eating certain foods, functional dyspepsia, postoperative gas expansion, peptic ulcers, spastic or irritable colon or diverticular disease. Infants have immature digestive systems, and swallowing air while crying or during feeding may cause gas or flatulence. Tiny bubbles form in the stomach or intestines, causing colic. Some known anti-flatulent agents are simethicone and / or activated dimethicone, which are designated to relieve flatulence and abdominal discomfort caused by excessive gastrointestinal gas. Simethicone and activated dimethicone reduce the surface tension of small bubbles, and the over-the-counter (OTC) indications of these active agents are "used to relieve painful bloating, as well as pressure and fullness, commonly known as gas in the digestive tract".

[0015] Simethicone and activated dimethicone are gastrointestinal protective agents with defoaming effects. They reduce the surface tension of gas bubbles, forming larger bubbles that burst to release gas. The released gas is naturally absorbed or eliminated. Simethicone and activated dimethicone do not reduce the amount of gas in the digestive tract; it only increases the rate at which gas leaves the body without any effect on intestinal motility, secretion, and elasticity. Simethicone is not absorbed by the body into the bloodstream and is therefore considered relatively safe.

[0016] Drotaverine has a very unpleasant bitter taste and residual aftertaste. The source of the bitterness is unknown. In some embodiments, masking the bitter taste of drotaverine is extremely important to ensure patient compliance. In addition, drotaverine hydrochloride is very susceptible to oxidation and pH, which leads to chemical instability. Although a variety of techniques have been tried to date to mask the taste of drotaverine hydrochloride without compromising stability by using methods such as solid dispersions, drug coatings or complexing with polymers, so far, no palatable, stable, oral drotaverine suspension has been reported in the literature.

[0017] The applicant's patent application WO2021181262A1 discloses a controlled-release tablet formulation of drotaverine or its salt.

[0018] US5154926A discloses reducing the bitterness of acetaminophen syrup by using water-soluble macromolecules with polyols and / or polymers of polyols having a molecular weight of 300 to 400. EP1025858A1 discloses reducing the bitterness of a base drug by combining propylene glycol with povidone and / or copovidone.

[0019] WO / 2019 / 075127 discloses a stable oral liquid formulation of midodrine comprising midodrine and sucralose. EP2268282B1 discloses an oral liquid formulation comprising deferiprone and a taste-masking composition comprising an effective amount of a sweetener (e.g., sucralose), a thickening and suspension aid (e.g., hydroxyethyl cellulose), a wetting agent (e.g., glycerol), and at least one flavoring agent. However, sucralose is an artificial sweetener, and it is prohibited for use in infants and children under 6 years of age.

[0020] US5616621A discloses a pharmaceutically acceptable taste-masking liquid excipient matrix for administering relatively large amounts of unpleasant tasting drugs. The patent document discloses that the viscosity of the liquid excipient matrix is ​​increased by adding a viscosity-increasing amount of a combination of usually solid polyethylene glycol and sodium carboxymethylcellulose to the liquid excipient matrix, thereby producing a taste-masking effect. Hari et al., 2018 (Asian J Pharm Clin Res, Vol 11, Issue 6, 2018, 289-297) discloses the preparation of an orally disintegrating taste-masking tablet of drotaverine hydrochloride using solid mixture technology. The document discloses that by using 3 cps of hydroxypropyl methylcellulose (HPMC) and FM1000 / calcium silicate was used as a carrier to prepare taste-masked drug-polymer solid mixtures of drotaverine hydrochloride using different drug-polymer ratios of 1:1, 1:5, 1:7.5 and 1:9. It is assumed that the increase in viscosity limits the contact of the drug with the tongue, thereby avoiding dilution and dissolution of the unpleasant-tasting drug by saliva. However, this approach is only moderately successful in reducing bitterness, especially at high drug loads. Although this method can reduce the initial bitterness, the bitter aftertaste after swallowing becomes prominent because the viscous formulation is more difficult to rinse, thus leaving some residual viscous liquid drug in the mouth for a long time after swallowing. In addition, water intake to avoid the bitter aftertaste reduces the viscosity and leads to dilution of the residual liquid drug and subsequent dissolution of the drug in the mouth.

[0021] The use of drug-loaded ion exchange resins to prepare dosage forms is known in the art. CN101288645A discloses a tilidine (pain relief) drug resin oral suspension and a method for preparing the same. US20050181050A1 discloses a modified release liquid containing drug-loaded ion exchange resin particles. Regulatory agencies are required to remove such solvents from drug products before ingestion. US20100166858A1 discloses a coated drug-ion exchange resin complex comprising a core consisting of a mixture of a drug-ion exchange resin complex and a release retardant. The coating disclosed in the patent document is a polyvinyl acetate polymer and a plasticizer. The methods disclosed in the literature employ complex and lengthy steps and use agents that may be harmful to children.

[0022] To date, there is no palatable, safe and stable concentrated oral suspension formulation of drotaverine or its salts for neonates, infants and children under 3 years of age.

[0023] Various methods of masking the bitter taste of drugs use one or more different flavoring methods. However, methods that are effective in masking the taste of a particular bitter drug are often not suitable for another drug.

[0024] Oral suspensions are considered suitable formulations, particularly for infants and very young children. Oral suspensions administered as drops provide a mechanism for delivering small volumes or low doses of drugs and other advantages, such as ease of swallowing and dosage flexibility. However, drotaverine hydrochloride degrades in large quantities in alkaline media, under conditions of higher oxidative stress, and in the presence of light. Therefore, it is necessary to develop a chemically stable, palatable suspension formulation of drotaverine or its salt, which has the advantages of accurate dose titration, ease of administration, and dosage flexibility. In some embodiments, the present disclosure is intended to provide an oral suspension formulation that is convenient to administer in a certain dosage range suitable for infants and children under 3 years of age. In addition, in some embodiments, the formulation should be free of harmful excipients and should have a longer shelf life.

[0025] Despite all the efforts made to date, there remains a need for stable and palatable pharmaceutical oral suspension formulations of antispasmodics. Summary of the invention

[0026] In some embodiments, the present disclosure provides an oral suspension comprising drotaverine or a salt thereof, wherein the concentration of drotaverine or a salt thereof is greater than 4 mg / mL. In some embodiments, the suspension comprises 5 mg / mL to 30 mg / mL of drotaverine or a salt thereof. In some embodiments, the suspension comprises a drotaverine-resin complex, wherein the ratio of drotaverine to resin is 1:2 to 1:6. In some embodiments, the drotaverine-resin complex comprises particles, wherein the size of the particles is in the range of 300 microns to 150 microns. In some embodiments, the resin is selected from Kyron 114, Kyron 314, Indion 204, Indion 234, Indion 294, or a combination thereof.

[0027] In some embodiments, the present disclosure provides an oral suspension comprising drotaverine or a salt thereof and an anti-flatulent agent. In some embodiments, the anti-flatulent agent is simethicone or activated dimethicone. In some embodiments, the suspension comprises 10 mg / mL to 80 mg / mL of simethicone or activated dimethicone.

[0028] In some embodiments, the present disclosure provides an oral suspension of drotaverine or its salt comprising a water-soluble polymer. In some embodiments, the water-soluble polymer comprises hydroxypropyl methylcellulose, polyvinyl pyrrolidone, gelatin, soluble starch, or a combination thereof. In some embodiments, the oral suspension comprises a solvent containing a sugar alcohol, a polyol, or a combination thereof. In some embodiments, the sugar alcohol is sorbitol or sorbitol (70% liquid). In some embodiments, the polyol is glycerol. In some embodiments, the solvent comprises a combination of sorbitol (70% liquid) and glycerol in a ratio of 1:1 to 9:1. In some embodiments, the oral suspension comprises a suspending agent containing sodium carboxymethylcellulose (Sod CMC), xanthan gum, or a combination thereof. In some embodiments, the amount of the suspending agent is 0.05% w / w to 3.0% w / w. In some embodiments, the suspension comprises a sweetener. In some embodiments, the sweetener is an artificial sweetener comprising aspartame, saccharin sodium, acesulfame potassium, sucralose, or a combination thereof. In some embodiments, the sweetener is a natural sweetener comprising sucrose, sorbitol or a combination thereof. In some embodiments, the suspension comprises flavorings, coloring agents, antioxidants, chelating agents, surfactants, wetting agents, pH adjusting agents, acidifiers, preservatives, solvents or a combination thereof. In some embodiments, the amount of the antioxidant is 0.05% w / w to 4.0% w / w. In some embodiments, the suspension is measured by high performance liquid chromatography (HPLC), and shows dosage uniformity, uniform dispersion and redispersibility.

[0029] In some embodiments, the present disclosure provides that when stored at 25°C to 30°C and 60% to 75% relative humidity (RH) as long-term storage conditions, the oral suspension of drotaverine or its salt is stable for 3 months. In some embodiments, when stored at 25°C to 30°C and 60% to 75% RH as long-term storage conditions, the suspension is stable for 6 months. In some embodiments, when stored at 25°C to 30°C and 60% to 75% RH as long-term storage conditions, the suspension is stable for 2 years. In some embodiments, when stored at 40°C and 75% RH as long-term storage conditions, the suspension is stable for 3 months. In some embodiments, when stored at 40°C and 75% RH as long-term storage conditions, the suspension is stable for 6 months.

[0030] In some embodiments, the present disclosure provides an oral suspension of drotaverine or a salt thereof that exhibits improved taste, improved aftertaste, improved palatability, or a combination thereof.

[0031] In some embodiments, the present disclosure provides a method for preparing an oral suspension of drotaverine or a salt thereof, comprising: (a) heating a certain amount of water and adding at least one preservative and ground sucrose, stirring the resulting mixture continuously until dissolved to obtain a solution; (b) cooling the solution to obtain a cooled solution; (c) adding at least one acidifier and at least one antioxidant to the cooled solution until dissolved to obtain a solution; (d) adding at least one wetting agent to the solution until dissolved to obtain a solution; (e) adding at least one stabilizer and a dispersion obtained by soaking at least one suspending agent in water until dissolved to obtain a large amount of solution; (f) filtering the drug-resin complex containing drotaverine or a salt thereof through a sieve, adding the large amount of solution obtained in step (e), stirring until dissolved to obtain a large amount of suspension; and (g) adding a certain amount of water to the large amount of suspension to obtain a suspension of drotaverine or a salt thereof. In some embodiments, the method comprises adding simethicone or activated dimethicone with drotaverine in step (f). In some embodiments, the drug-resin complex comprises Kyron 114, Kyron 314, Indion 204, Indion 234, or Indion 294, or a combination thereof. In some embodiments, the drug-resin complex comprising drotaverine or a salt thereof is mixed in a ratio of 1:2 to 1:6. In some embodiments, the drug-resin complex is air dried or dried using a drying device. In some embodiments, the dried drug-resin complex has less than 5.0% w / w water. In some embodiments, the sieve used in step (f) comprises a mesh, wherein the mesh is no greater than 300 microns.

[0032] In some embodiments, the present disclosure provides a method of treating abdominal pain comprising administering to a subject in need thereof an oral dosage form comprising drotaverine or a salt thereof and simethicone.

[0033] In some embodiments, the present disclosure provides a use of a liquid dosage form comprising drotaverine or a salt thereof and simethicone for treating abdominal pain, comprising administering the liquid dosage form to a subject in need thereof. DETAILED DESCRIPTION

[0034] In some embodiments, the present disclosure provides a stable oral palatable suspension formulation of an antispasmodic agent. In some embodiments, the formulation has the advantage of precise dose titration, exhibits excellent dose uniformity, redispersibility characteristics, ease of administration, and dose flexibility. In some embodiments, the formulation of the present disclosure is suitable for breast-fed infants and children under 3 years old because it does not contain alcohol and artificial sweeteners. In some embodiments, the present disclosure is intended to deliver an appropriate dose in a small volume for the target age group, thereby providing flexibility in dosage in the hands of pediatricians.

[0035] In some embodiments, the formulation exhibits physical and chemical stability over the entire shelf life of the product under recommended long-term storage conditions. In some embodiments, the disclosure also provides methods for preparing oral suspension formulations. In some embodiments, the disclosure also provides uses of oral suspension formulations.

[0036] In some embodiments, the present disclosure provides oral suspension dosage forms of drotaverine that exhibit improved taste, aftertaste, and palatability. The term "taste" as used herein refers to the sensation of taste experienced when the tongue of a subject contacts the dosage form. The term "aftertaste" as used herein refers to the sensation of taste experienced in the mouth after administration of the dosage form. For example, after administration of drotaverine, there is typically a lasting aftertaste. The term "palatability" as used herein refers to the physical sensation of the dosage form when the dosage form is in the mouth of a subject, such as the mouthfeel of the dosage form. In some embodiments, the oral suspension dosage forms disclosed herein show improved taste, aftertaste, and palatability compared to currently available drotaverine suspensions.

[0037] To mask the high bitterness and residual aftertaste of drotaverine, various techniques were evaluated, including the use of ingredients such as flavorings, sweeteners, amino acids, polymer coatings, gelatin, gelatinized starch, liposomes, lecithin or lecithin-like substances, surfactants, salts or polymeric films, as well as the use of conventional granulation, spray congealing with lipids, inclusion complexes with cyclodextrins, freeze drying processes, multiple emulsions. However, the final products from these techniques failed to produce the desired product performance parameters, including taste masking and palatability. Ion exchange resins were then further evaluated.

[0038] Although some of the unpleasant taste of drotaverine was masked by using ion exchange technology, the resulting product did not provide acceptable palatability characteristics because the resulting product was too bland. Therefore, additional studies targeting the particle size and ratio of the drug-resin complex were conducted. The combined approach of ion exchange resins mixed with excipients and flavoring agents produced a palatable oral suspension formulation of the present disclosure. In some embodiments, the formulations of the present disclosure are safe and acceptable for neonates, infants, and children less than 3 years old.

[0039] Drotaverine hydrochloride degrades extensively in alkaline media, higher oxidative stress conditions and in the presence of light. The ion exchange complexation technology not only masks the bitter taste of drotaverine, but also surprisingly and unexpectedly exhibits excellent chemical stability throughout the shelf life of the suspension formulation. In some embodiments, the disclosed formulations use very few excipients, all of which are completely safe, economical and readily available for pediatric patients.

[0040] In some embodiments, the disclosed formulation provides a rapid release of drotaverine to provide relief to the target pediatric patient population. In some embodiments, despite the use of ion exchange resin technology, the disclosed formulation of the present disclosure has no negative impact on drug dissolution release and bioavailability. In some embodiments, the disclosed oral suspension provides a mechanism for drug dose delivery in a small volume, which can be used for very young children and infants. In addition, in some embodiments, the disclosed oral suspension exhibits excellent dose uniformity and redispersibility characteristics. In some embodiments, HPLC is used to measure dose uniformity and redispersibility. Shake the bottle containing the suspension product to form a uniform suspension, then take out the suspension sample and analyze it by HPLC to measure the content uniformity of the suspension. In some embodiments, the disclosed formulation is based on an easily scalable and cost-effective manufacturing process.

[0041] In some embodiments, the present disclosure provides a pharmaceutical combination of an antispasmodic agent and one or more anti-flatulent agents and one or more pharmaceutically acceptable excipients. In some embodiments, the present disclosure also provides a method for preparing the pharmaceutical combination. In some embodiments, the present disclosure also provides uses of the pharmaceutical combination.

[0042] In some embodiments, the present disclosure relates to a fixed dose pharmaceutical formulation comprising drotaverine hydrochloride and simethicone or dimethicone and one or more pharmaceutically acceptable excipients.

[0043] The inventors of the present disclosure attempted to dissolve drotaverine hydrochloride in a dispersion medium comprising sorbitol liquid, glycerol and water in a ratio of 1:1:1 to 3:2:1, respectively. However, the drug reprecipitated when stored in the above-mentioned dispersion medium. In order to obtain a physically and chemically stable product with a good shelf life, the inventors addressed this precipitation of drotaverine in the proposed dispersion medium. In order to avoid the precipitation of drotaverine, the inventors added stabilizers to the dispersion medium. To this end, various possible stabilizers were evaluated, including water-soluble polymers, which can appropriately increase the solubility of drotaverine in the proposed dispersion medium and thereby stabilize the suspension formulation to prevent drug precipitation.

[0044] Some exemplary water-soluble polymers include hydroxypropyl methylcellulose (HPMC), polyvinyl pyrrolidone, gelatin and soluble starch. Among these water-soluble polymers, polyvinyl pyrrolidone (POVIDONE) is preferred. Because polyvinyl pyrrolidone includes soluble grade and insoluble grade, it is found that soluble grade provides optimal stability. Usually, soluble polyvinyl pyrrolidone is synthesized by polymerization. Free radical polymerization in water uses hydrogen peroxide as initiator. Polyreaction can stop at any time, and this makes it possible to produce the soluble polyvinyl pyrrolidone of about any molecular weight.

[0045] As the brand name of polyvinylpyrrolidone in the market, The family is now a group of common polyvinylpyrrolidone-based excipients used in the pharmaceutical industry. They have a variety of applications in oral formulations; the functions of oral formulations include rapid disintegration, sustained drug release, solubility, and bioavailability enhancement. Examples of soluble grades of (povidone) are 12PF, 17PF, 25, 30, 90F and VA64 (copovidone).

[0046] The inventors of the present disclosure surprisingly and unexpectedly found no precipitation problems in one of the initial experiments in which a low molecular weight povidone grade was used. PF12, although povidone grades are commonly used as tablet binders in wet granulation processes for solid oral dosage forms. (PF 12, 17, 25, 30 and 90) Additional experiments were performed at levels ranging from about 2% to about 8%.

[0047] Based on the above experiments, using povidone ( PF12) solves the precipitation problem for the proposed dispersion medium for suspension. Several suspension products with different levels of sorbitol, glycerol, povidone as stabilizer, sucrose, suspending agent (e.g., xanthan gum and sodium carboxymethylcellulose), flavoring agent and drotaverine hydrochloride were prepared and analyzed. A direct mixing process using an agitator and a homogenizer is used to prepare the suspension. Although the inventors are able to obtain a physically stable suspension, the final product is still unpalatable due to the high bitterness of drotaverine hydrochloride. Although artificial sweeteners such as aspartame, saccharin sodium, acesulfame potassium and sucralose are available, these artificial sweeteners have not been widely studied in infants and children under 3 years old. In some embodiments, the preparation of the present disclosure comprises a natural sweetener. In some embodiments, the natural sweetener comprises sucrose, sorbitol or a combination thereof.

[0048] In addition to the bitter taste of the suspension, chemical stability issues were observed in the form of high impurity levels in the suspension product due to degradation of drotavirine beyond the limits recommended by global regulatory guidelines.

[0049] To solve the problem of bitter taste, ion exchange resins are used for taste masking. Ion exchange resins are solid and appropriately insoluble high molecular weight polyelectrolytes that can exchange their equally charged mobile ions with the surrounding medium. Ion exchange resins are insoluble matrices (or support structures), usually in the form of small (1mm to 2mm diameter) beads, usually white or yellow, made from an organic polymer matrix. The material has a highly developed surface pore structure that is a location that is easy to capture and release ions. The capture of ions occurs only when other ions are released simultaneously; therefore, the process is called ion exchange. There are many different types of ion exchange resins that are manufactured to selectively prefer one or several different types of ions.

[0050] In some embodiments, the ion exchange resin comprises a cross-linked polyacrylic acid polymer or a salt thereof, including a Kyron grade polymer. In some embodiments, the Kyron grade polymer comprises Kyron 114 or Kyron 314 (Corel PharmaChem, Ahmedabad). In some embodiments, the ion exchange resin comprises an Indion grade polymer. In some embodiments, the Indion grade polymer comprises Indion 204, Indion 234, or Indion 294 (Ion Exchange India Ltd., Mumbai).

[0051] Shows that the positively charged drug (D + ) and cation exchange resin (RCOO - ) The representation of the ion exchange process of the acid-base complex formed is described as follows:

[0052] D + +RCOO - →RCOO-D (Oral preparations)

[0053] RCOO-D+H + +Cl - →D + +RCOOH+Cl - (Gastric Preparation)

[0054] Ion exchange resins mask the taste of drugs because the resin-drug complex formed barely elutes the drug in the neutral pH of the oral cavity. Thus, the taste of the drug is masked in the oral cavity without disrupting the release profile of the drug in the stomach.

[0055] Several studies were conducted to develop a suitable drotaverine drug-resin complex that would result in masked bitterness and residual aftertaste. The drug and a suitable grade of ion exchange resin were selected based on the initial studies, wherein the drug to polymer ratio was 1:1 to 1:8. The ion exchange resin was first mixed in water and stirred for a sufficient time using a suitable method. Thereafter, drotaverine or its salt was slowly added to the resin mixture and stirred for a sufficient time to obtain the resinate. The resulting resinate was separated by filtration using a suitable sieve. The filtered resin complex was then washed until the filtrate obtained after washing contained almost no unbound or free drotaverine drug. The percentage of free drotaverine drug not bound to the resin should not exceed 2% w / w of the input drug at the beginning of the complexation process; preferably less than 1% w / w. Thereafter, the drug-resin complex was used directly to prepare a suspension or it could be dried overnight at room temperature. Drying of the drug-resin complex can be performed using a suitable drying apparatus, which may include, but is not limited to, a tray dryer or a fluidized bed dryer, until a target water content of less than 5.0% w / w is reached. The dried drug-resin complex was tested for free drotaverine drug. The free drug content should not exceed 2.0%.

[0056] The dried drug-resin complex is then used to formulate an oral suspension by using suitable additives, which may include suspending agents, sweeteners, flavoring agents, coloring agents, antioxidants, chelating agents, surfactants, wetting agents, antifoaming agents, pH adjusters, acidifiers, preservatives, solvents or mixtures thereof.

[0057] In some embodiments, the oral suspension comprises a solvent. In some embodiments, the solvent is a sugar alcohol, a polyol, or a combination thereof. In some embodiments, the sugar alcohol is sorbitol. In some embodiments, sorbitol is a 70% liquid dispersion. In some embodiments, the polyol is ethylene glycol, glycerol, or a combination thereof. In some embodiments, the solvent is sorbitol (70% liquid) and glycerol, and the ratio of sorbitol (70% liquid): glycerol is 1:1 to 9:1. In some embodiments, the ratio of sorbitol (70%): glycerol is 2:1 to 8:1.

[0058] In some embodiments, the oral suspension comprises a suspending agent. In some embodiments, the suspending agent is sodium carboxymethylcellulose (Sod CMC), xanthan gum, or a combination thereof. In some embodiments, the amount of the suspending agent is 0.05% w / w to 3.0% w / w. In some embodiments, the amount of the suspending agent is 0.08% w / w to 2.0% w / w.

[0059] Sugar alcohols are fairly safe and the recommended intake of sugar alcohols is 10 to 15 grams per day. Suitable sugar alcohols include sorbitol used as a 70% liquid dispersion.

[0060] Suitable polyols include ethylene glycol, glycerol, etc. In some embodiments, the oral suspension comprises an acidulant, an acidifier, a pH adjuster, or a combination thereof. In some embodiments, the acidulant, the acidifier, or the pH adjuster is citric acid, fumaric acid, lactic acid, maleic acid, malic acid, tartaric acid, or a combination thereof.

[0061] In some embodiments, the oral suspension comprises an antioxidant. In some embodiments, the antioxidant is butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, sodium hyposulfite, propyl gallate, ascorbic acid, glycine, cysteine, or a combination thereof. In some embodiments, the amount of the antioxidant is 0.05% w / w to 4% w / w. In some embodiments, the amount of the antioxidant is 0.1% w / w to 3.0% w / w.

[0062] In some embodiments, the oral suspension comprises a wetting agent. In some embodiments, the wetting agent is a long alkyl chain sulfonate, a long alkyl chain sulfate, a quaternary ammonium salt, a fatty alcohol, a fatty acid ester, a polyoxyethylene derivative of a fatty acid ester, or a combination thereof. In some embodiments, the long alkyl chain sulfate is sodium dodecylbenzene sulfonate, sodium lauryl sulfate, dialkyl sodium sulfosuccinate, or a combination thereof. In some embodiments, the fatty alcohol is a laurate, a cetyl ester, a sterol ester, a glycerate, or a combination thereof. In some embodiments, polyoxyethylene derivatives are synthesized by polymerization by adding ethylene oxide to obtain sorbitan anhydride fatty acid esters. These are nonionic hydrophilic surfactants, commonly referred to as tweens or polysorbates, such as polysorbate 20, 60, and 80.

[0063] In some embodiments, the oral suspension comprises a preservative. In some embodiments, the preservative is a paraben or its sodium salt. In some embodiments, the paraben is methyl paraben, propyl paraben or its sodium salt. In some embodiments, the preservative is benzyl alcohol, thimerosal or a combination thereof.

[0064] In some embodiments, the oral suspension comprises a flavoring agent. In some embodiments, the flavoring agent is a natural flavoring agent, a natural fruit flavoring agent, an artificial flavoring agent, an artificial fruit flavoring agent, a flavor enhancer, or a combination thereof. In some embodiments, the flavoring agent used is strawberry, cherry, orange, peppermint, blackcurrant, banana, raspberry, red fruit, wild berry, caramel, or a combination thereof.

[0065] In addition, some flavoring supply companies also provide special flavorings that are called bitter masking agents. They are usually a combination of sweeteners and flavorings, to mask the unpleasant taste of low to medium bitterness. In some embodiments, the oral suspension comprises an effervescent agent, which can be added to improve mouthfeel. In some embodiments, the effervescent agent is sodium bicarbonate, citric acid or a combination thereof. In some embodiments, in addition to other taste masking techniques, flavorings or effervescent agents are also used to achieve the target taste characteristics of the product.

[0066] In some embodiments, the oral suspension comprises a colorant. Colorants or pigments can be incorporated to provide attractive colors for pharmaceutical preparations. In some embodiments, colorants are considered safe for human consumption by relevant government regulatory agencies, and chemical incompatibility with other ingredients is avoided. In some embodiments, the colorant is Sunset Yellow FCF (known as FD&C Yellow No. 6 and Tartrazine in the U.S.), which is a synthetic tartrazine azo dye. It is also known as FD&C Yellow No. 5.

[0067] As an alternative manufacturing method according to some embodiments, the drug resin complex in the wet stage itself can be directly formulated as an oral suspension formulation using certain of the additives mentioned above, without drying the drug resin complex.

[0068] Based on a large number of experiments with different combinations, the ratio of the drug-resin complex was finally determined to be 1:2 to 1:6, and the particle size of the drug-resin complex particles was finally determined after the drug-resin complexation and drying steps. In order to ensure smooth texture and palatability, the particle size of the dried drug-resin complex particles is fully reduced with appropriate grinding parameters to ensure that the final suspension product is free of grit and provides a smooth feeling when swallowing. Based on development research, in some embodiments, the development of a suitable particle size should be less than 50 mesh, ASTM (equivalent to about 300 microns), preferably 60 mesh, ASTM (equivalent to about 250 microns) or more preferably about 100 mesh, ASTM (equivalent to about 150 microns).

[0069] Once the desired particle size specifications for the drug-resin complex are determined according to some embodiments, further formulation experiments are performed on the suspension formulation.

[0070] In some embodiments, the prepared drug-resin complex is used to prepare a suspension formulation.

[0071] The method for preparing a stable palatable suspension formulation according to some embodiments of the present disclosure comprises the following steps:

[0072] 1. Heat a quantity of water to an appropriate temperature and pH, then add one or more preservatives and ground sucrose with continuous stirring until dissolved to obtain a solution.

[0073] 2. Cooling the solution obtained in step (1) to an appropriate temperature to obtain a cooled solution.

[0074] 3. Add one or more acidifiers and antioxidants to the cooled solution of step (2) at a suitable stirring speed until dissolved to obtain a solution.

[0075] 4. Add one or more wetting agents to the solution of step (3) under suitable stirring speed for a sufficient time to avoid excessive foaming until it is sufficiently dispersed to obtain a solution.

[0076] 5. Add a dispersion obtained by soaking one or more suspending agents in a sufficient amount of water to the solution obtained in step (4) for a sufficient period of time, preferably overnight, and then add one or more stabilizers, stirring until they are dissolved to obtain a dispersion.

[0077] 6. Filter the drug-resin complex through a suitable sieve and then add the drug-resin complex to the dispersion of step (5) and stir for sufficient time until it is uniformly dispersed to obtain a bulk suspension.

[0078] 7. Add the anti-flatulent agent, sweetener and colorant to the bulk suspension of step (6) at an appropriate stirring speed for a sufficient time to obtain a suspension product.

[0079] 8. Adjust the volume of the suspension product of step (7) with a certain amount of water to obtain the final suspension product.

[0080] In some embodiments, the final suspension product is filled into suitable containers using a suitable filling machine. In some embodiments, the filled containers can be sealed and optionally sterilized before or after sealing.

[0081] In some embodiments, the present disclosure provides a pharmaceutical combination product comprising simethicone, dimethicone, or a mixture thereof, and drotaverine or a salt thereof.

[0082] In some embodiments, the disclosed formulations achieve improved taste characteristics using drug-resin complexes in combination with flavoring agents, sweeteners, stabilizers and other additives. Accelerated stability conditions were also used to evaluate the chemical stability of the disclosed formulations. Even though drug-resin complexation technology was initially evaluated with the goal of taste masking, the inventors of the present disclosure unexpectedly observed in some embodiments that the chemical stability of the suspension product was significantly improved compared to the suspension product prepared without the use of ion exchange resins. Even the addition of antioxidants alone does not provide a stable product unless an ion exchange resin is used.

[0083] The impurity levels observed in the resulting suspension product were within the impurity target limits from the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines.

[0084] The terms "stable", "stability" or "stabilized" mean that the dosage form is able to maintain product performance test parameters, such as the amount of ingredients, the amount of related substances, without significant changes compared to the initial level.

[0085] The term "significant change" means a change of 5% or more from the initial result. For example, if the initial amount of an ingredient is 98%, then a significant change would be an amount of 93% or less of that ingredient. If a product is stable under accelerated conditions (40°C / 75%RH) for 6 months without significant change, then its shelf life can be specified as at least 2 years or 24 months.

[0086] In some embodiments, the oral suspension is stable for at least three months under long-term storage conditions. In some embodiments, the oral suspension is stable for at least 6 months under long-term storage conditions. In some embodiments, long-term storage conditions include 25°C to 30°C at 60% to 75% RH. In some embodiments, long-term storage conditions include 15°C to 30°C at 60% to 75% RH.

[0087] In some embodiments, the flavoring used in the present disclosure is the flavoring of the type and amount required for the palatability of the enhanced preparation.Exemplary flavorings that can be used for the present disclosure include natural flavorings, natural fruit flavorings, artificial flavorings, artificial fruit flavorings, flavor enhancers or their mixtures.Exemplary natural flavorings, artificial flavorings or their mixtures include mint (such as peppermint or spearmint) and menthol.Exemplary natural fruit flavorings, artificial fruit flavorings or their mixtures include cherry, grape, berry (such as strawberry, raspberry, blackberry, blueberry, cranberry), blood orange, melon, banana, citrus and vanilla.Although flavorings are usually provided as the minor component of the taste masking of effective dose, to provide palatable flavorings, preferably at least one flavoring is added in some embodiments, and more preferably, more than one flavoring can be used in some embodiments.

[0088] In some embodiments, colorants or pigments may be incorporated to provide an attractive color to the suspension formulation. Suitable colorants are well known to those skilled in the art and are those colorants deemed safe for human consumption by relevant governmental regulatory agencies and avoid chemical incompatibilities with other ingredients.

[0089] In some embodiments, the oral suspension formulations of the present disclosure exhibit faster drug release compared to currently marketed oral suspension products.

[0090] The following non-limiting examples are provided as representative of suitable formulations consistent with the objects, features, and advantages of the present disclosure.

[0091] Example 1: Method for preparing drug-resin complex

[0092] First, the ion exchange resin is mixed in about 4 to 8 volumes of water and stirred for about 30 to 45 minutes at 45 to 65 degrees Celsius and a pH of 5.5 to 7.0 using a mechanical stirrer. Then, drotaverine hydrochloride is slowly added to the resin mixture and stirred for at least 2 to 4 hours to obtain a drug-resin complex. The drug-resin complex is prepared by using a drug and resin in a ratio of 1:2 to 1:6. The obtained drug-resin complex is separated by filtration using a sieve #80 (ASTM) to obtain a filtered resin complex. Thereafter, the filtered drug-resin complex is washed with water until the filtrate obtained after washing contains almost no unbound drotaverine drug.

[0093] The obtained drug-resin complex was used directly for preparing suspension. In another experiment, the drug-resin complex was dried overnight at room temperature. The drug-resin complex was dried until a target water content of less than 5.0% w / w was reached. The dried drug-resin complex was tested for free drotaverine drug. The free drug content should not be more than 2.0%.

[0094] The dried drug-resin complex can be used immediately for the preparation of an oral suspension by using suitable additives, or can be stored for later use. Suitable additives are added, including but not limited to sweeteners, flavoring agents, coloring agents, antioxidants, chelating agents, surfactants, wetting agents, defoaming agents, pH regulators, acidifiers, preservatives, co-solvents and mixtures thereof. See Examples 3-11 below.

[0095] After drug-resin complexation and an optional drying step, the drug-resin complex is milled until a target particle size of less than 50 mesh, American Standard Testing Sieve Series (ASTM) (equivalent to about 300 microns), 60 mesh, ASTM (equivalent to about 250 microns), or about 100 mesh, ASTM (equivalent to about 150 microns) is achieved.

[0096] Example 2: Method for preparing suspension formulation from drug-resin complex

[0097] The drug-resin complex prepared in Example 1 was used to prepare a suspension formulation product.

[0098] In some embodiments, the method of preparing a stable palatable suspension formulation of the present disclosure comprises the following steps:

[0099] 1. Heat about 30% of the target batch size of water to 45 to 65 degrees Celsius and 5.5 to 7.0 pH in the initial stage and then add methylparaben, propylparaben and ground sucrose under continuous stirring until dissolved to obtain a solution.

[0100] 2. Cool the solution obtained in step (1) to 25 to 40 degrees Celsius to obtain a cooled solution.

[0101] 3. Add citric acid and sodium metabisulfite to the cooled solution of step (2), first add citric acid, then add sodium metabisulfite, stir at 500 rpm to 1000 rpm until dissolved to obtain a solution.

[0102] 4. Add polysorbate 80 to the solution of step (3) at an appropriate speed of 300 rpm to 500 rpm for 15 to 20 minutes to avoid excessive foaming until it is fully dispersed to obtain a solution.

[0103] 5. Soak xanthan gum or sodium CMC in water at about 1% to 2% of the target batch size for sufficient time, preferably overnight, before adding it to the main portion of the suspension. Then add the dispersion obtained by the above steps to the solution obtained in step (4), followed by the addition of povidone and stirring until a bulk solution is obtained.

[0104] 6. The drug-resin complex was filtered through a sieve #80 (ASTM) and then added to the bulk solution of step (5) and stirred for 20 to 30 minutes until it was uniformly dispersed to obtain a bulk suspension.

[0105] 7. Add simethicone, sorbitol colorant and flavoring to the large amount of suspension in step (6) at 1000 rpm to 2000 rpm for 20 to 30 minutes to obtain a suspension product.

[0106] 8. Adjust the volume of the suspension product of step (7) with water in an amount of about 5% to 10% of the target batch size to obtain the final suspension product.

[0107] In some embodiments, the final suspension product is filled into bottles of about 100 mL to 200 mL capacity by hand, however, a semi-automatic or fully automatic filling machine may be used. In some embodiments, the filled bottles are sealed using a ROPP sealing machine.

[0108] The following exemplary formulations containing drotaverine were prepared by the preparation methods described in Examples 1 and 2 above, by using different ratios of drug and resin in the drug-resin complex.

[0109] Example 3: An exemplary formulation containing drotaverine was prepared by using a drug-resin complex having a ratio of drotaverine to resin of 1:2.5.

[0110] Table 1: Formulations containing drotaverine-resin complex (1:2.5)

[0111]

[0112]

[0113] Example 4: An exemplary formulation containing drotaverine was prepared by using a drug-resin complex having a ratio of drotaverine to resin of 1:3.

[0114] Table 2: Formulations containing drotaverine-resin complex (1:3)

[0115]

[0116]

[0117] Example 5: An exemplary formulation containing drotaverine was prepared by using a drug-resin complex having a ratio of drotaverine to resin of 1:4.

[0118] Table 3: Formulations containing drotaverine-resin complex (1:4)

[0119]

[0120] Example 6: An exemplary formulation of drotaverine was prepared by employing a drug-resin complex having a ratio of drotaverine to resin of 1:4.

[0121] Table 4: Formulations containing drotaverine-resin complex (1:4)

[0122]

[0123] Example 7: An exemplary formulation of drotaverine was prepared by employing a drug-resin complex having a ratio of drotaverine to resin of 1:4.

[0124] Table 5: Formulations containing drotaverine-resin complex (1:4)

[0125]

[0126]

[0127] Example 8: An exemplary formulation of drotaverine was prepared by employing a drug-resin complex having a ratio of drotaverine to resin of 1:5.

[0128] Table 6: Formulations containing drotaverine-resin complex (1:5)

[0129]

[0130]

[0131] Example 9: An exemplary formulation of drotaverine was prepared by employing a drug-resin complex having a ratio of drotaverine to resin of 1:2.

[0132] Table 7: Formulations containing drotaverine-resin complex (1:2)

[0133]

[0134]

[0135] Example 10: An exemplary formulation of drotaverine was prepared by employing a drug-resin complex having a ratio of drotaverine to resin of 1:3.

[0136] Table 8: Formulations containing drotaverine-resin complex (1:3)

[0137]

[0138] Example 11: An exemplary formulation of drotaverine was prepared by employing a drug-resin complex having a ratio of drotaverine to resin of 1:4.

[0139] Table 9: Formulations containing drotaverine-resin complex (1:4)

[0140]

[0141] Embodiment 12:

[0142] Examples 3 to 11 show oral suspension (20 mg / mL) formulations. An in vitro drug dissolution study of a representative formulation (Example 8) was evaluated according to the following test conditions, and the formulation showed faster drug release compared to the currently marketed 20 mg / 5 mL oral suspension product. Therefore, the suspensions disclosed according to these examples show rapid drug release, indicating that they will lead to faster pain relief than currently available oral suspension products.

[0143] Table 10: Comparison of dissolution data of drotaverine oral suspension of commercially available suspensions versus drugs of the present disclosure.

[0144]

[0145]

[0146] Example 13: Stability Data

[0147] In view of the accelerated stability data using the ICH guidelines (40°C ± 2°C / 75% RH ± 5% RH), the disclosed suspension formulations of the listed examples show good chemical and physical stability. The impurity levels observed in the resulting product are within the target limits of impurities of the ICH guidelines. The accelerated stability data of one of the representative formulations with drug-resin complexes is given in the following table (Table 11), compared with the formulation prepared without resin complexation technology (Table 12):

[0148] Table 11

[0149]

[0150]

[0151] Table 12

[0152]

[0153] It is evident from the data in Tables 11 and 12 that the pharmaceutical resin formulation surprisingly and unexpectedly improves the stability of drotaverine. The pharmaceutical resin formulation exhibited low impurity levels in the accelerated stability study.

[0154] Although the subject matter of the present invention has been described herein with reference to certain preferred embodiments thereof, other embodiments are possible. For illustrative purposes, some embodiments of the present disclosure are in oral liquid form, such as suspensions, solutions, emulsions, elixirs, cough syrups, mixtures, and contain drotaverine or a salt thereof as an antispasmodic agent. In addition, for illustrative purposes, some embodiments of the present disclosure are suitable for neonates, infants, and children under 6 years of age. However, those skilled in the art will appreciate that the scope of the present disclosure extends to combinations and formulations suitable for other age groups, administered orally in other forms, and may include other antispasmodic agents known in the art.

Claims

1. An oral suspension comprising drotaverine or a salt thereof, wherein the concentration of drotaverine or a salt thereof is greater than 4 mg / mL.

2. The oral suspension of claim 1, wherein the liquid oral dosage form comprises a drotaverine-resin complex wherein the ratio of drotaverine to resin is from 1:2 to 1:

6.

3. The oral suspension of claim 2, wherein the drotaverine-resin complex comprises particles, wherein the size of the particles is 300 microns to 150 microns.

4. The oral suspension of claim 2, wherein the resin is selected from Kyron 114, Kyron 314, Indion 204, Indion 234, Indion 294 or a combination thereof.

5. The oral suspension of claim 4, wherein the resin comprises Kyron 114.

6. The oral suspension according to any one of claims 1 to 5, wherein the dosage form further comprises an anti-flatulent agent.

7. The oral suspension of claim 6, wherein the anti-flatulent agent is simethicone or activated dimethicone.

8. The liquid oral suspension according to any one of claims 1 to 7, wherein the drotaverine is the hydrochloride salt.

9. The oral suspension according to any one of claims 1 to 8, wherein the dosage form comprises 5 mg / mL to 30 mg / mL of drotaverine or a salt thereof.

10. The oral suspension of any one of claims 1 to 9, wherein the dosage form comprises 10 mg / mL to 80 mg / mL simethicone or activated dimethicone.

11. The oral suspension according to any one of claims 1 to 10, wherein the dosage form comprises a water soluble polymer.

12. The oral suspension of claim 11, wherein the water-soluble polymer comprises hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, soluble starch, or a combination thereof.

13. The oral suspension of any one of claims 1 to 12, wherein the suspension comprises a solvent, wherein the solvent comprises a sugar alcohol, a polyol, or a combination thereof.

14. The oral suspension of claim 13, wherein the solvent comprises a sugar alcohol, and the sugar alcohol is sorbitol or sorbitol (70% liquid).

15. The oral suspension of claim 13 or 14, wherein the solvent comprises a polyol and the polyol is glycerol.

16. The oral suspension of claim 13, wherein the solvent comprises sorbitol (70% liquid) and glycerol in a ratio of 1:1 to 9:

1.

17. An oral suspension as claimed in claim 16, wherein the ratio of sorbitol (70% liquid) to glycerol is from 2:1 to 8:

1.

18. The oral suspension of any one of claims 1 to 17, wherein the suspension comprises a suspending agent, wherein the suspending agent comprises sodium carboxymethylcellulose (Sod CMC), xanthan gum, or a combination thereof.

19. The oral suspension of claim 18, wherein the suspending agent is present in an amount of 0.05% w / w to 3.0% w / w.

20. The oral suspension of claim 19, wherein the suspending agent is present in an amount of 0.08% w / w to 2.0% w / w.

21. The oral suspension of any one of claims 1 to 20, wherein the dosage form comprises a sweetener.

22. The oral suspension of claim 21, wherein the sweetener is an artificial sweetener comprising aspartame, saccharin sodium, acesulfame potassium, sucralose, or a combination thereof.

23. The oral suspension of claim 21, wherein the sweetener is a natural sweetener comprising sucrose, sorbitol, or a combination thereof.

24. The oral suspension of any one of claims 1 to 23, wherein the dosage form comprises a flavoring agent, a coloring agent, an antioxidant, a chelating agent, a surfactant, a wetting agent, a pH adjusting agent, an acidulant, a preservative, a solvent, or a combination thereof.

25. The oral suspension of claim 24, wherein the amount of the antioxidant is from 0.05% w / w to 4% w / w.

26. The oral suspension of claim 25, wherein the amount of the antioxidant is from 0.1% w / w to 3.0% w / w.

27. The oral suspension of any one of claims 1 to 26, wherein the dosage form exhibits dose uniformity, uniform dispersion and redispersibility as measured by high performance liquid chromatography.

28. An oral suspension comprising drotaverine hydrochloride, Kyron 114, simethicone, xanthan gum, povidone (Kollidon 12PF), sucrose, citric acid, Tween 80, sodium metabisulfite, sorbitol 70%, glycerol, methylparaben, propylparaben and flavoring, wherein the drotaverine hydrochloride and Kyron 114 comprise a drug-resin complex, and wherein the ratio of the drotaverine hydrochloride to Kyron 114 is 1:

3.

29. The oral dosage form of any one of claims 1 to 28, wherein the dosage form is stable for 3 months when stored at 40°C and 75% RH as accelerated storage conditions.

30. The oral dosage form of any one of claims 1 to 29, wherein the dosage form is stable for 6 months when stored at 40°C and 75% RH as accelerated storage conditions.

31. The oral suspension according to any one of claims 1 to 30, wherein the suspension is stable for 3 months when stored at 25°C to 30°C and 60% to 75% RH as long term storage conditions.

32. The oral suspension of claim 31, wherein the suspension is stable for 6 months when stored at 25°C to 30°C and 60% to 75% RH as long-term storage conditions.

33. The oral suspension of claim 32, wherein the dosage form is stable for 2 years when stored at 25°C to 30°C and 60% to 75% RH as long term storage conditions.

34. The oral suspension of any one of claims 1 to 31, wherein the liquid oral dosage form exhibits improved taste.

35. The oral suspension of any one of claims 1 to 31, wherein the liquid oral dosage form exhibits an improved aftertaste.

36. The oral suspension of any one of claims 1 to 31, wherein the liquid oral dosage form exhibits improved palatability.

37. A method for preparing an oral suspension of drotaverine or a salt thereof, comprising: a. heating a certain amount of water, and adding at least one preservative and ground sucrose, and continuously stirring the resulting mixture until dissolved to obtain a solution; b. cooling the solution to obtain a cooled solution; c. adding at least one acidulant and at least one antioxidant to the cooled solution until dissolved to obtain a solution; d. adding at least one wetting agent to the solution until dissolved to obtain a solution; e. adding at least one stabilizer and a dispersion obtained by soaking at least one suspending agent in water until dissolved to obtain a bulk solution; f. The drug-resin complex containing drotaverine or a salt thereof is filtered through a sieve, and the large amount of solution obtained in step (e) is added and stirred until dissolved to obtain a large amount of suspension; and g. adding a certain amount of water to the bulk suspension to obtain a suspension of drotaverine or its salt.

38. The method of claim 37, wherein the method comprises adding simethicone or activated dimethicone with drotaverine in step (f).

39. The method of claim 37 or 38, wherein the drug-resin complex comprises Kyron 114, Kyron 314, Indion 204, Indion 234 or Indion 294 or a combination thereof.

40. The method of any one of claims 37 to 39, wherein the drug-resin complex comprising drotaverine or a salt thereof is mixed in a ratio of 1:2 to 1:

6.

41. The method of any one of claims 37 to 40, wherein the drug-resin complex is air dried or dried using a drying device.

42. The method of any one of claims 37 to 41, wherein the dried drug-resin complex has less than 5.0% w / w water.

43. The method of any one of claims 37 to 42, wherein the screen used in step (f) comprises a mesh, wherein the mesh is no larger than 300 microns.

44. A method of treating abdominal pain comprising administering to a subject in need thereof an oral dosage form comprising drotaverine or a salt thereof and simethicone, wherein the oral suspension comprises the oral suspension of any one of claims 1 to 36.

45. Use of a liquid dosage form comprising drotaverine or a salt thereof and simethicone for treating abdominal pain, comprising administering the liquid dosage form to a subject in need thereof, wherein the oral suspension comprises any one of claims 1 to 36.

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