A stable oral pharmaceutical liquid preparation of an antispasmodic agent

Abstract

The present invention provides an oral suspension formulation of drotaverine or a salt thereof, methods for producing them, and their use in therapy.

Description

Technical Field

[0001] The present disclosure relates to a stable oral pharmaceutical suspension formulation of an antispasmodic agent. More specifically, the present disclosure relates to a stable oral pharmaceutical suspension formulation of drotaverine or a salt thereof. The present disclosure also relates to a method for preparing such a formulation and its use.

Background Art

[0002] Background For pediatric patients, the oral administration route of drugs is preferred. Unlike adults, for whom oral solid dosage forms such as tablets and capsules are acceptable to the majority of patients, pediatric patients, including neonates (within 1 month after birth), infants, toddlers, and children, cannot swallow normal tablets. They prefer very small dosages to avoid volume overload. Therefore, an oral suspension dosage form such as a suspension administered as drops is considered a suitable formulation for infants and toddlers. The drops of the oral suspension enable delivery of a small amount, delivery of a low dose of the drug, ease of swallowing, and flexibility of administration.

[0003] In the development of age-appropriate pharmaceuticals for infants and children, it is necessary not only to understand the preferences for various formulations, flavors, and textures of the product, but also to understand the physical and biochemical differences between children and adults. In the design of pediatric formulations, factors such as minimizing the impact on the lifestyle of children, reducing the frequency of administration, providing a palatable dosage form, enabling individualized dosing or grouping of dosages for effective treatment, providing sufficient bioavailability, avoiding toxic excipients, providing a convenient and reliable administration route, and using a robust manufacturing process at a minimum cost may be considered.

[0004] Taste is an important and decisive parameter in administering oral preparations. Newborn infants are born with sensitive taste buds, which may be more widely distributed than those of adults. Newborns can distinguish sweet and bitter tastes using the taste buds located on the back of the tonsils, the throat, and the tongue. Newborns generally prefer sweet tastes such as breast milk. Some evidence indicates that the preference for sweet tastes is innate. T.R. Maone et al., A New Method for Delivering a Taste without Fluids to Preterm and Term Infant, 23 Dev., Psychobiol., 179 (1990). Bitter taste is considered the opposite of sweet taste and is usually regarded as bad and undesirable. Many drugs are inherently bitter, and bitterness is one of the problems encountered during drug development. The bitterness of drugs can prevent patients, especially infants and children, from wanting to or being able to swallow such preparations.

[0005] Merely blocking the taste may not be sufficient to block the bitterness of the drug, and a more complex formulation may be required. Excipients are usually used to improve taste, shelf life, and / or the manufacturing process. Since many excipients are known to be harmful to newborns, the selection of excipients in neonatal pharmaceuticals is another important factor to be monitored. Excipients are generally regarded as "inactive ingredients", but many excipients that are pharmacologically inactive in adults may be toxic to newborns and children. For example, using a small amount of ethanol as a solvent in formulations such as diazepam oral solution is not a problem for adults, but its use in this population is inappropriate because it may lead to CNS (central nervous system) depression in newborns. Furthermore, the inclusion of propylene glycol in formulations used in newborns (such as cefirizine oral solution) has raised concerns about ototoxicity and CNS toxicity in the past (Linakis et al., 2016; Clinical Pharmacokinetics, volume 55, pages 185-196). Therefore, certain excipients such as ethanol, propylene glycol, benzyl alcohol, and parabens are not recommended because they may delay the development of the organs of newborns and children. The excipients used in product development must be safe and acceptable for use in newborns and children.

[0006] Abdominal pain is a common problem for infants and young children and can be a difficult symptom to treat. The causes of pain are diverse, and abdominal pain occurs from newborns to adults. Dividing this population into age groups of 0-1 year, 1-6 years, 6-11 years, and 11-18 years is useful for designing prescriptions suitable for diagnosis and pain treatment. Due to the wide age range of the pediatric population, it is unlikely that a single prescription is appropriate within an 18-year range, and multiple products may be required. Solid oral dosage forms can be administered to older children aged 6-11 years or 11-18 years, but infants and children under 6 years old cannot easily swallow solid oral medications. In these age groups, liquid oral formulations allow for accurate dosing and are easy to administer.

[0007] Drotaverine hydrochloride is a benzylisoquinoline derivative and an analogue 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 a very potent antispasmodic agent that acts directly on smooth muscle and has no anticholinergic side effects. It is used in the treatment of various gastrointestinal disorders associated with smooth muscle spasm, biliary dyskinesia, and vasomotor disorders. Drotaverine is adsorbed on the cell surface and changes the cell membrane potential and permeability. It has a dual mechanism of action that inhibits the enzyme phosphodiesterase IV (PDE IV) and the calcium-binding protein calmodulin (CAM). This increases the cyclic adenosine monophosphate (cAMP) level in smooth muscle, thus reducing the concentration of free calcium ions (Ca 2+ ). The combination of a decrease in Ca 2+ ions and inhibition of calmodulin inhibits the formation of the "calmodulin-calcium complex" (CAM-Ca2+). This process inhibits the myosin light chain kinase enzyme (MLCK), causing dephosphorylation of the actomyosin phosphate complex and relaxation of smooth muscle.

[0009] Some pharmacokinetic parameters of drotaverine (e.g., elimination, half-life, plasma clearance, renal clearance, and apparent volume of distribution) may not be affected by the route of drug administration. The pharmacokinetic parameters of immediate-release (IR) drotaverine tablets (80 mg) have been studied. [O.O. Bolaji et al., Pharmacokinetics and Bioavailability of Drotaverine in Humans, 21 Eur. J. Drug Metab. Pharmacokinet. 217 (1996)]. This drug is mainly excreted via non-renal routes since renal clearance accounts for only 0.31 ± 0.13% of total plasma clearance. Absolute bioavailability varied and differed among subjects, ranging from 24.5 to 91%, with an average of 58.2 ± 18.2% (mean ± SD). Due to the large variability in bioavailability after oral administration of drotaverine hydrochloride, it has been suggested that there are significant individual differences in the therapeutic response to this drug. In pharmacokinetic and bioavailability studies, drotaverine was shown to be rapidly absorbed, i.e., the onset of action of an 80 mg strength IR tablet occurs within 12 minutes after oral administration. The peak plasma level occurs 1 to 3 hours later, while the elimination half-life was 7 to 11.95 hours. Drotaverine is considered to be very safe in toxicity tests, and the reported oral LD50 of drotaverine exceeds 1000 mg per kg of body weight, so the therapeutic index is wide.

[0010] Currently, drotaverine is available as a conventional IR tablet, and tablets of 40 mg and 80 mg strengths are used to relieve and prevent smooth muscle spasms of various organs regardless of their functions and innervations. The approved daily dose of drotaverine tablets is 120 - 240 mg (administered in 2 - 3 divided doses) for adults, 80 - 200 mg (administered in 2 - 5 divided doses) for children aged 6 - 18 years, and 40 - 120 mg (administered in 2 - 3 divided doses) for children aged 1 - 6 years. In children, the oral suspension of drotaverine is also used for the treatment of abdominal pain. This is available in two strengths of 10 mg / 5 mL and 20 mg / 5 mL. The dosage of drotaverine suspension is 0.5 mL / kg body weight or 1 mL / kg body weight. Children aged 1 - 6 years are administered a maximum of 120 mg in 3 divided doses per day, and children aged 6 - 12 years are administered 0.5 mL / kg body weight or >1 mL / kg body weight in 3 divided doses per day for a maximum of 200 mg. The currently marketed strengths of drotaverine suspension (10 mg or 20 mg per 5 mL) cannot be easily administered to infants and children under 3 years of age due to the large volume per administration unit. Therefore, it is necessary to develop a suitable concentrated form of drotaverine preparation that can be easily administered in the form of an oral suspension or spray and is reduced to a maximum of 1 mL if possible.

[0011] Drotaverine, alone or in combination, contributes very effectively to the relief of spasms accompanied by pain due to various gastrointestinal, urinary, gynecological, and / or obstetric diseases, and is the first-choice medicine for emergency medicine in abdominal pain relief.

[0012] Drotaverine suspension can be administered for the treatment of acute abdominal pain in children. Children usually have poor awareness of the onset of the disease and the location of the pain and cannot effectively explain or verbalize the pain characteristics, severity, duration, or spread of the pain, which are very important for diagnosis. For example, a child may not be able to explain the type of pain resulting from acute appendicitis, which is very common in children. Drotaverine, a PDE IV inhibitor, can be used to selectively relieve abdominal muscle pain without blocking other symptoms of acute abdominal pain. Due to this characteristic, drotaverine is unique compared to other existing antispasmodic / anticholinergic drugs.

[0013] Drotaverine has been proven to relieve abdominal pain without the side effects associated with anticholinergic drugs. It is an effective and safe medication in managing recurrent abdominal pain in children. Most commonly, it is known to be used for gastrointestinal problems in preschool and school-age children. Drotaverine is non-toxic, has minimal side effects, and can be administered to children without long-term problems.

[0014] Irritable bowel syndrome (IBS) is often accompanied by flatulence, which causes pain and discomfort to the patient. In some embodiments, the antiflatulence active ingredient is useful for treating conditions where gas retention is a problem, such as excessive air swallowing by infants, colic, certain food ingestion, functional dyspepsia, postoperative gas distension, peptic ulcer, spastic or irritable colon, or diverticulosis. Infants have an immature digestive system and may swallow air while crying or feeding, which can cause gas or flatulence. Small air bubbles form in the stomach or intestines, causing colic. Some known antiflatulence agents include simethicone and / or activated dimethicone, which are indicated for relieving flatulence and abdominal discomfort caused by excess gastrointestinal gas. Simethicone and activated dimethicone reduce the surface tension of small gas bubbles. The over-the-counter (OTC) indication for these active substances is "the relief of painful bloating, pressure and feelings of fullness, commonly known as gas in the digestive tract."

[0015] Simethicone and activated dimethicone are gastrointestinal protectants with antifoaming properties. They reduce the surface tension of gas bubbles, causing larger bubbles to form and burst, releasing the gas. The released gas is either absorbed or naturally excreted. Simethicone and activated dimethicone do not reduce the amount of gas in the digestive tract, they only increase the rate at which gas leaves the body, they do not affect intestinal motility, secretions, or tone. Simethicone is not absorbed into the bloodstream and is therefore considered relatively safe.

[0016] Drotaveline has a very unpleasant bitter taste and a lingering aftertaste. The cause of the bitterness is unknown. In some embodiments, blocking the bitter taste of drotaveline is extremely important to ensure patient compliance. Furthermore, drotaveline hydrochloride is very susceptible to oxidation and the influence of pH, which causes chemical instability. So far, various techniques such as solid dispersion, drug coating, or complex formation with polymers have been tried to block the taste of drotaveline hydrochloride without compromising stability, but a delicious and stable oral drotaveline suspension has not been reported in the literature so far.

[0017] The patent application WO2021181262A1 of the applicant of the present application discloses a controlled-release tablet of drotaveline or a salt thereof.

[0018] US5154926A discloses reducing the bitter taste of paracetamol syrup by using a water-soluble polymer in combination with a polyhydric alcohol and / or a polymer of a polyhydric alcohol having a molecular weight of 300 to 400. EP1025858A1 discloses reducing the bitter taste of a basic drug by combining propylene glycol with povidone and / or copovidone.

[0019] WO / 2019 / 075127 discloses a stable oral liquid formulation of midodrine containing midodrine and sucralose. EP2268282B1 discloses an oral pharmaceutical liquid formulation containing deferiprone and a taste masking composition, and the composition contains an effective amount of a sweetening agent such as sucralose, a thickening and suspending aid (such as hydroxyethyl cellulose), a humectant (such as glycerin), and at least one flavoring agent. However, sucralose is an artificial sweetener and is prohibited for use in infants and children under 6 years old.

[0020] US5616621A discloses a pharmaceutically acceptable taste masking liquid excipient base for administering a relatively large amount of an unpleasant-tasting agent. This patent document discloses that the taste masking effect is produced by increasing the viscosity of the liquid excipient base by adding an amount of increase in viscosity of a mixture of usually solid polyethylene glycol and sodium carboxymethylcellulose to the liquid excipient base. Hari et al., 2018 (Asian J Pharm Clin Res, Vol 11, Issue 6, 2018, 289-297) discloses a formulation of orally disintegrating taste masking tablets of drotaverine hydrochloride using solid mixture technology. This literature discloses the preparation of a taste masking drug-polymer solid mixture of drotaverine hydrochloride using hydroxypropylmethylcellulose (HPMC) 3 cps and Rxcipient® FM1000 / calcium silicate (Rxcipient®) as carriers and varying the drug-polymer ratio at 1:1, 1:5, 1:7.5, and 1:9. It is thought that the increase in viscosity limits the contact of the agent with the tongue, thereby avoiding the dilution and dissolution of the bad-tasting intake agent by saliva. However, this approach has only a slight effect in reducing bitterness, especially when the drug content is high. This approach may reduce the initial bitterness, but the thick formulation is difficult to swallow, and a viscous liquid drug remains in the mouth for a long time after swallowing, resulting in a prominent bitter aftertaste after swallowing. Furthermore, drinking water to avoid the bitter aftertaste reduces the viscosity, dilutes the residual liquid drug, and then the drug dissolves in the mouth.

[0021] The preparation of dosage forms using ion exchange resins filled with drugs is known in the art. CN101288645A discloses a tilidine (analgesic) drug-resin oral suspension and its manufacturing method. US20050181050A1 discloses a modified release solution containing ion exchange resin particles filled with drugs. Regulatory authorities require the removal of such solvents from pharmaceuticals prior to ingestion. US20100166858A1 discloses a coated drug-ion exchange resin composite comprising a core consisting of a drug-ion exchange resin composite mixed with a release retardant. The coating disclosed in this patent document is a polyvinyl acetate polymer and a plasticizer. The process disclosed in this document employs complex and time-consuming steps and uses drugs that are potentially harmful to children.

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

[0023] In various approaches to masking the bitterness of drugs, one or more different flavoring methods are used. However, approaches that are effective in masking the taste of a particular bitter drug often cannot be applied to other drugs.

Summary of the Invention

Problems to be Solved by the Invention

[0024] An oral suspension is considered to be a particularly suitable formulation for infants and very young children. An oral suspension administered as a drop provides a mechanism for delivering a small amount or low dose of a drug, as well as advantages such as ease of swallowing and flexibility of administration. However, drotaverine hydrochloride decomposes significantly in the presence of an alkaline medium, high oxidative stress conditions, and light. Therefore, it is necessary to develop a chemically stable and palatable suspension formulation of drotaverine or its salts that has the advantages of accurate dosing, ease of administration, and flexibility of administration. In some embodiments, the present disclosure aims to provide an oral suspension formulation that facilitates administration in various dosage ranges suitable for infants and children under 3 years of age. Further, in some embodiments, this formulation should not contain harmful excipients and should have a longer shelf life.

[0025] Despite all the efforts made to date, the need for a stable and palatable pharmaceutical oral suspension formulation of an anticonvulsant remains.

Means for Solving the Problems

[0026] Overview 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 exceeds 4 mg / mL. In some embodiments, the suspension comprises 5 - 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 granules, wherein the size of the granules ranges from 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 drotaveline or a salt thereof and an anti-flatulence agent. In some embodiments, the anti-flatulence agent is simeticone or activated dimethicone. In some embodiments, the suspension comprises 10 to 80 mg / mL of simeticone or activated dimethicone.

[0028] In some embodiments, the present disclosure provides an oral suspension of drotaveline or a salt thereof comprising a water-soluble polymer. In some embodiments, the water-soluble polymer comprises hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, soluble starch, or a combination thereof. In some embodiments, the oral suspension comprises a solvent comprising a sugar alcohol, a polyhydric alcohol, or a combination thereof. In some embodiments, the sugar alcohol is sorbitol or sorbitol (70% liquid). In some embodiments, the polyhydric alcohol is glycerin. In some embodiments, the solvent comprises a combination of sorbitol (70% liquid) and glycerin in a ratio of 1:1 to 9:1. In some embodiments, the oral suspension comprises a suspending agent comprising sodium carboxymethylcellulose (Sod CMC), xanthan gum, or a combination thereof. In some embodiments, the suspending agent is in an amount of 0.05% to 3.0% w / w. In some embodiments, the suspension comprises a sweetening agent. In some embodiments, the sweetening agent is an artificial sweetening agent comprising aspartame, sodium saccharin, acesulfame K, sucralose, or a combination thereof. In some embodiments, the sweetening agent is a natural sweetening agent comprising sucrose, sorbitol, or a combination thereof. In some embodiments, the suspension comprises a flavoring agent, a coloring agent, an antioxidant, a chelating agent, a surfactant, a wetting agent, a pH adjuster, an acidifying agent, a preservative, a solvent, or a combination thereof. In some embodiments, the amount of the antioxidant is 0.05% to 4.0% w / w. In some embodiments, the suspension exhibits dose uniformity, uniform dispersion, and redispersibility as measured by high performance liquid chromatography (HPLC).

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

[0030] In some embodiments, the present disclosure provides an oral suspension of drotaverine or a salt thereof that exhibits an 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, the method comprising: (a) heating a quantity of water and adding at least one preservative and crushed sucrose, and continuously stirring the resulting mixture until dissolved to obtain a solution; (b) cooling the solution to obtain a cooled solution; (c) adding to the cooled solution at least one acidifying agent and at least one antioxidant until dissolved to obtain a solution; (d) adding to the solution at least one wetting agent until dissolved to obtain a solution; (e) adding at least one stabilizer and a dispersion obtained by immersing at least one suspending agent in water until dissolved to obtain a bulk solution; (f) sieving a drug-resin complex containing drotaverine or a salt thereof to fractionate, adding the bulk solution obtained in step (e), and stirring until dissolved to obtain a bulk suspension; and (g) adding a quantity of water to the bulk suspension to obtain a suspension of drotaverine or a salt thereof. In some embodiments, the method comprises adding simethicone or activated dimethicone together 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 containing 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 contains less than 5.0% w / w water. In some embodiments, the sieve used in step (f) comprises a mesh, where the mesh is 300 microns or less.

[0032] In some embodiments, the present disclosure provides a method for treating abdominal pain, the method 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 for using a liquid dosage form comprising drotaveline or a salt thereof and simeticone in the treatment of abdominal pain, comprising administering the liquid dosage form to a subject in need thereof.

Mode for Carrying Out the Invention

[0034] Detailed Description In some embodiments, the present disclosure provides a stable and palatable oral suspension formulation of an antispasmodic agent. In some embodiments, this formulation has the advantages of accurate dosage determination, excellent dosage uniformity, redispersion properties, ease of administration, and flexibility of administration. In some embodiments, the formulations of the present disclosure are suitable for infants being breastfed and children under 3 years of age because they do not contain alcohol or artificial sweeteners. In some embodiments, the present disclosure is aimed at delivering a small amount of a dosage suitable for the target age group, thereby providing flexibility in administration by a pediatrician.

[0035] In some embodiments, the formulation exhibits physical and chemical stability throughout the shelf life of the product according to the recommended long-term storage conditions. In some embodiments, the present disclosure also provides a method for preparing an oral suspension formulation. In some embodiments, the present disclosure also provides for the use of an oral suspension formulation.

[0036] In some embodiments, the present disclosure provides an oral suspension dosage form of drotaveline with improved taste, aftertaste, and palatability. As used herein, the term "taste" is used to refer to the sensory perception of flavor when the subject's tongue contacts the dosage form. As used herein, the term "aftertaste" is used to refer to the sensory perception of flavor felt in the mouth after administration of the dosage form. For example, the aftertaste typically persists sufficiently after administration of drotaveline. As used herein, the term "palatability" is used to refer to the physical sensation of the dosage form when in the subject's mouth, such as the tactile sensation of the dosage form. In some embodiments, the oral suspension dosage forms disclosed herein exhibit improved taste, aftertaste, and palatability compared to currently available drotaveline suspensions.

[0037] To block the very bitter and long-lasting aftertaste of drotaverine, the use of ingredients such as flavoring agents, sweetening agents, amino acids, polymer coatings, gelatin, gelatinized starch, liposomes, lecithin or lecithin-like substances, surfactants, salts, or polymer films, and various techniques including conventional granulation, spray congealing with lipids, inclusion complexes with cyclodextrins, freeze-drying processes, the use of multiple emulsions, etc. were evaluated. However, the final products by these techniques did not bring about desirable product performance parameters such as taste masking and palatability. Subsequently, ion exchange resins were further evaluated.

[0038] Part of the unpleasant taste of drotaverine was blocked by the use of ion exchange technology, but the resulting product was too tasteless to provide acceptable palatability characteristics. Therefore, additional tests targeting the particle size and the ratio of the drug-resin complex were conducted. By a combination approach of blending ion exchange resins with excipients and flavoring agents, the palatable oral suspension formulations of the present disclosure were obtained. In some embodiments, the formulations of the present disclosure are safe and acceptable from a global regulatory perspective for neonates, infants, and children under 3 years old.

[0039] Drotaverine hydrochloride decomposes significantly in an alkaline medium, under high oxidative stress conditions, and in the presence of light. The ion exchange complex formation technology not only blocks the bitterness of drotaverine but, surprisingly and unexpectedly, shows excellent chemical stability over the entire shelf life of the suspension formulation. In some embodiments, the disclosed formulations use little excipient, and these formulations are all completely safe, economical, and readily available for pediatric patients.

[0040] In some embodiments, the disclosed formulations provide rapid release of drotaverine and provide relief to the targeted pediatric patient population. In some embodiments, the disclosed formulations of the present disclosure do not adversely affect drug dissolution release and bioavailability despite using ion exchange resin technology. In some embodiments, the disclosed oral suspensions provide a mechanism for delivering small drug dosages, which is useful for young children and infants. Further, in some embodiments, the disclosed oral suspensions exhibit excellent dosage uniformity and redispersion characteristics. In some embodiments, dosage uniformity and redispersibility are measured using HPLC. Bottles containing the suspension product are shaken to form a uniform suspension, and then samples of the suspension are taken and analyzed by HPLC to measure the content uniformity of the suspension. In some embodiments, the disclosed formulations are 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-flatulence agents with 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 the use of the pharmaceutical combination.

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

[0043] The inventors of the present disclosure attempted to solubilize drotaverine hydrochloride in a dispersion medium containing sorbitol solution, glycerin, and water in ratios ranging from 1:1:1 to 3:2:1, respectively. However, when stored in the above dispersion medium, the drug reprecipitated. To obtain a physically and chemically stable product with a good shelf life, the inventors solved this precipitation of drotaverine in the proposed dispersion medium. To avoid the precipitation of drotaverine, the inventors added a stabilizer to the dispersion medium. For this purpose, various possible stabilizers were evaluated, including water-soluble polymers that can appropriately increase the solubility of drotaverine in the proposed dispersion medium and thus stabilize the suspension formulation to prevent precipitation of the drug.

[0044] Typical examples of water-soluble polymers include hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone, gelatin, and soluble starch. Among these water-soluble polymers, polyvinylpyrrolidone (povidone) is preferred. Polyvinylpyrrolidone has both soluble and insoluble grades, and it has been found that the soluble grade has the highest stability. Usually, soluble polyvinylpyrrolidone is synthesized by polymerization. In free radical polymerization in water, hydrogen peroxide is used as an initiator. Since the polymerization reaction can be stopped at any time, soluble polyvinylpyrrolidone with almost any molecular weight can be produced.

[0045] Kollidon® is available on the market as a brand name for polyvinylpyrrolidone, and the Kollidon® family is currently a set of common excipients based on polyvinylpyrrolidone used in the pharmaceutical industry. These have various uses in oral formulations. The functions of oral formulations include rapid disintegration, sustained drug release, solubility, and improved bioavailability. Examples of the soluble grades of Kollidon® (povidone) are Kollidon® 12PF, 17PF, 25, 30, 90F, and Kollidon® VA64 (copovidone).

[0046] The inventors of the present disclosure surprisingly and unexpectedly discovered that there was no precipitation problem in one of the first experiments using the low molecular weight povidone grade Kollidon® PF12. However, povidone grades are typically used as tablet binders in the wet granulation process of solid oral dosage forms. Additional experiments were carried out using different grades of Kollidon® (PF12, 17, 25, 30, and 90) at levels in the range of about 2% to about 8% in the proposed dispersion medium.

[0047] Based on the above experiments, the precipitation problem was solved by using povidone (Kollidon® PF12) as the proposed dispersion medium for suspension. Several suspension products having different levels of sorbitol, glycerin, povidone as a stabilizer, sucrose, suspending agents (such as xanthan gum and sodium carboxymethylcellulose), flavoring agents, and drotaverine hydrochloride were prepared and analyzed. The suspension was prepared using a direct mixing process with a stirrer and a homogenizer. The inventors were able to achieve a physically stable suspension, but the final product remained unpalatable due to the very bitter taste of drotaverine hydrochloride. Artificial sweeteners such as aspartame, sodium saccharin, acesulfame K, and sucralose are available, but these artificial sweeteners have not been widely tested in infants and children under 3 years of age. In some embodiments, the formulations of the present disclosure include natural sweeteners. In some embodiments, the natural sweeteners include sucrose, sorbitol, or a combination thereof.

[0048] In addition to the bitterness of the suspension, chemical stability problems were observed in the form of high impurity levels in the suspension product due to the degradation of drotaverine beyond the limits recommended by worldwide regulatory guidelines.

[0049] To solve the problem of bitterness, an ion exchange resin was used for taste masking. An ion exchange resin is a solid, moderately insoluble, high molecular weight polyvalent electrolyte that can exchange mobile ions of the same charge as the surrounding medium. Ion exchange resins are usually insoluble matrices (or support structures) in the form of small (1 - 2 mm in diameter), usually white or yellowish - tinted beads made from an organic polymer substrate. This material has a highly developed structure of surface pores, which are sites for easily capturing and releasing ions. Since ion capture occurs only when there is simultaneous release of other ions, this process is called ion exchange. There are several different types of ion exchange resins, which are manufactured to selectively prefer one or more different types of ions.

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

[0051] The following shows an ion - exchange process demonstrating acid - base complex formation formed from a positively charged drug (D + ) and a cation - exchange resin (RCOO - ). D + + RCOO - → RCOO - D (in - mouth formulation) RCOO - D + H + + Cl - → D + + RCOOH + Cl - (in - stomach formulation)

[0052] Since the resin-drug complex formed hardly or does not elute the drug at neutral pH in the oral cavity, the ion exchange resin blocks the taste of the drug. Therefore, the taste of the drug is blocked in the oral cavity without interfering with the drug release characteristics in the stomach.

[0053] To develop a suitable drotaverine drug-resin complex that provides masking of bitterness and the residual aftertaste, several tests were conducted. Based on initial tests where the ratio of drug to polymer ranged from 1:1 to 1:8, the drug and an appropriate grade of ion exchange resin were selected. The ion exchange resin was first mixed in water and stirred for a sufficient time using appropriate means. Thereafter, drotaverine or its salt was slowly added to the resin mixture and stirred for a sufficient time to obtain a resin-treated product. The obtained resin-treated product was separated by filtration through an appropriate sieve. Thereafter, the filtered resin complex was washed until there was hardly any unbound or free drotaverine drug remaining in the filtrate obtained after washing. The proportion of free drotaverine drug not bound to the resin should not exceed 2% w / w of the drug input at the start of the complex formation process, preferably less than 1% w / w. Thereafter, the drug-resin complex may be used directly for the preparation of a suspension or dried overnight at room temperature. Drying of the drug-resin complex can be carried out using an appropriate drying device (including but not limited to a tray dryer or a fluidized bed dryer) until the target moisture content is less than 5.0% w / w. The dried drug-resin complex is tested for free drotaverine drug. The content of free drug should not exceed 2.0%.

[0054] Next, the dried drug-resin complex is used for the preparation of an oral suspension using appropriate additives, which may include suspending agents, sweetening agents, flavoring agents, coloring agents, antioxidants, chelating agents, surfactants, wetting agents, defoaming agents, pH adjusters, acidifying agents, preservatives, solvents, or mixtures thereof.

[0055] In some embodiments, the oral suspension contains a solvent. In some embodiments, the solvent is a sugar alcohol, a polyhydric alcohol, or a combination thereof. In some embodiments, the sugar alcohol is sorbitol. In some embodiments, the sorbitol is a 70% liquid dispersion. In some embodiments, the polyhydric alcohol is glycol, glycerin, or a combination thereof. In some embodiments, the solvent is sorbitol (70% liquid) and glycerin, and the ratio of sorbitol (70% liquid):glycerin is from 1:1 to 9:1. In some embodiments, the ratio of sorbitol (70%):glycerin is from 2:1 to 8:1.

[0056] In some embodiments, the oral suspension contains 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 ranges from 0.05% to 3.0% w / w. In some embodiments, the amount of the suspending agent ranges from 0.08% to 2.0% w / w.

[0057] Sugar alcohols are quite 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.

[0058] Suitable polyhydric alcohols include glycol, glycerin, etc. In some embodiments, the oral suspension contains an acidifying agent, an acidulant, a pH adjuster, or a combination thereof. In some embodiments, the acidifying agent, the acidulant, or the pH adjuster is citric acid, fumaric acid, lactic acid, maleic acid, malic acid, tartaric acid, or a combination thereof.

[0059] In some embodiments, the oral suspension contains an antioxidant. In some embodiments, the antioxidant is butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, sodium thiosulfate, propyl gallate, ascorbic acid, glycine, cysteine, or a combination thereof. In some embodiments, the amount of the antioxidant ranges from 0.05 to 4% w / w. In some embodiments, the amount of the antioxidant is 0.1 to 3.0% w / w.

[0060] In some embodiments, the oral suspension contains 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 dodecylbenzenesulfonate, sodium lauryl sulfate, sodium dialkyl sulfosuccinate, or a combination thereof. In some embodiments, the fatty alcohol is a lauryl ester, a cetyl ester, a steryl ester, a glyceryl ester, or a combination thereof. In some embodiments, the polyoxyethylene derivative is synthesized by addition of ethylene oxide by polymerization to obtain sorbitan fatty acid esters. These are generally nonionic hydrophilic surfactants known as Tweens or polysorbates, for example, polysorbate 20, 60, and 80.

[0061] In some embodiments, the oral suspension contains a preservative. In some embodiments, the preservative is a parabens or its sodium salt. In some embodiments, the parabens are methylparaben, propylparaben, or their sodium salts. In some embodiments, the preservative is benzyl alcohol, thimerosal, or a combination thereof.

[0062] In some embodiments, the oral suspension contains 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, mint, loquat, banana, raspberry, dragon fruit, wild berry, caramel, or a combination thereof.

[0063] Furthermore, several companies that supply flavoring agents usually also offer a special flavoring agent commonly referred to as a bitterness masking flavoring agent. These are usually a combination of a sweetening agent and a flavoring agent for masking the unpleasant taste of low to moderate levels of bitter active substances. In some embodiments, the oral suspension contains a foaming agent, which can be added to improve palatability. In some embodiments, the foaming agent is sodium bicarbonate, citric acid, or a combination thereof. In some embodiments, a flavoring agent or a foaming agent is used in addition to other taste masking techniques to achieve the targeted taste characteristics of the product.

[0064] In some embodiments, the oral suspension contains a coloring agent. A coloring agent or colorant can be incorporated to give an attractive color to the pharmaceutical formulation. In some embodiments, the coloring agent is considered safe for human consumption by the relevant government regulatory agencies and avoids chemical incompatibility with other ingredients. In some embodiments, the coloring agent is Sunset Yellow FCF, a synthetic lemon yellow azo dye (known as FD&C Yellow No. 6 and Tartrazine in the United States). This is also known as FD&C Yellow 5.

[0065] As an alternative manufacturing method according to some embodiments, the drug-resin complex itself in the wet stage can be directly formulated as an oral suspension formulation using the specific additives above without drying the drug-resin complex.

[0066] Based on extensive testing of various combinations, drug-resin composites with ratios of 1:2 to 1:6 were prepared, and after the formation and drying processes of the drug-resin composites, the particle size of the drug-resin composites was finalized. To ensure a smooth texture and palatability, the particle size of the dried drug-resin composite granules was made small enough with appropriate grinding parameters so that the final suspension product was free of roughness and provided a smooth feel when swallowed. Based on development testing, in some embodiments, the appropriate particle size should be less than 50 mesh, ASTM (equivalent to about 300 microns), preferably less than 60 mesh, ASTM (equivalent to about 250 microns), or more preferably less than about 100 mesh, ASTM (equivalent to about 150 microns).

[0067] According to some embodiments, after determining the desired particle size specifications of the drug-resin composite, further formulation experiments of the suspension formulation were conducted.

[0068] In some embodiments, the prepared drug-resin composite was used in the manufacture of a suspension formulation.

[0069] A method for preparing a stable and palatable suspension formulation according to some embodiments of the present disclosure includes the following steps:

[0070] 1. Heating a certain amount of water to an appropriate temperature and pH, and subsequently adding one or more preservatives and ground sucrose, and continuously stirring until dissolved to obtain a solution. 2. Cooling the solution obtained in step (1) to an appropriate temperature to obtain a cooled solution. 3. Adding one or more acidifying agents and antioxidants to the cooled solution of step (2) at an appropriate stirring speed until dissolved to obtain a solution. 4. Adding one or more wetting agents to the solution of step (3) at an appropriate stirring speed for a sufficient time while avoiding excessive foaming and until it is sufficiently dispersed to obtain a solution. 5. After immersing one or more suspending agents in a sufficient amount of water, adding one or more drugs to the suspension for a sufficient time, preferably overnight, adding the resulting dispersion to the solution obtained in step (4), and then adding one or more stabilizers and stirring until they are dissolved to obtain a dispersion. 6. Separating the drug-resin complex with a suitable sieve, and then adding the drug-resin complex to the dispersion of step (5) and stirring for a sufficient time until it is uniformly dispersed to obtain a bulk suspension. 7. Adding an anti-flatulence agent, a sweetening agent, and a coloring agent to the bulk suspension of step (6) at a suitable stirring speed for a sufficient time to obtain a suspension product. 8. Adjusting the volume of the suspension product of step (7) with the amount of water to obtain a final suspension product.

[0071] In some embodiments, the final suspension product is filled into a suitable container using a suitable filling machine. In some embodiments, the filled container is sealed and may be optionally sterilized before or after sealing.

[0072] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising simethicone, dimethicone, or a mixture thereof together with drotaverine or a salt thereof.

[0073] In some embodiments, the disclosed formulations achieve improved taste characteristics by using a drug-resin complex in combination with a flavoring agent, a sweetening agent, a stabilizer, and other additives. The disclosed formulations were also evaluated for chemical stability using accelerated stability conditions. The drug-resin complex formation technology was initially evaluated for the purpose of taste masking, but the inventors of the present disclosure surprisingly observed that, in some embodiments, the chemical stability of the present suspension product is significantly improved compared to the suspension product produced without using an ion exchange resin. Without using an ion exchange resin, a stable product could not be obtained by adding only an antioxidant.

[0074] The impurity levels observed in the resulting suspension product were within the target limits for impurities according to the guidelines of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH).

[0075] The terms "stable", "stability", or "stabilization" mean that the dosage form can maintain the product performance test parameters such as the amount of components and the amount of related substances without significant change from the initial levels.

[0076] The term "significant change" means a change of 5% or more from the initial results. For example, if the initial amount of a component is 98%, a significant change would be the amount of that component dropping to 93% or less. If the product is stable without significant change for 6 months under accelerated conditions (40°C / 75%RH), a shelf life of at least 2 years or 24 months can be assigned.

[0077] In some embodiments, the oral suspension is stable for at least 3 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, the long-term storage conditions are 25 - 30°C, 60 - 75%RH. In some embodiments, the long-term storage conditions are 15 - 30°C, 60 - 75%RH.

[0078] In some embodiments, the flavoring agents used in the present disclosure were of a type and in an amount desirable for enhancing the taste of the formulation. Examples of flavoring agents that can be used in the present disclosure include natural flavoring agents, natural fruit flavoring agents, artificial flavoring agents, artificial fruit flavoring agents, flavor enhancers, or mixtures thereof. Examples of natural flavoring agents, artificial flavoring agents, or mixtures thereof include mint (such as peppermint or spearmint) and menthol. Examples of natural fruit flavoring agents, artificial fruit flavoring agents, or mixtures thereof include cherry, grape, berries (such as strawberry, raspberry, blackberry, blueberry, cranberry, etc.), orange blade, melon, banana, citrus fruits, and vanilla. The flavoring agent is generally provided as a minor component of the taste masking composition in an amount effective to impart a pleasant taste to the suspension formulation, but in some embodiments, the addition of at least one flavoring agent is preferred, and more preferably, two or more flavoring agents can be used in some embodiments.

[0079] In some embodiments, a coloring agent or colorant can be incorporated to impart an attractive color to the suspension formulation. Suitable coloring agents are well known to those skilled in the art and are considered safe for human consumption by the relevant government regulatory agencies and avoid chemical incompatibility with other components.

[0080] In some embodiments, the disclosed oral suspension formulations of the present disclosure exhibit faster drug release compared to currently commercially available oral suspension products.

Examples

[0081] The following non-limiting examples are provided as representative suitable formulations consistent with the objectives, features, and advantages of the present disclosure.

[0082] Example 1: Method for Preparing a Drug-Resin Composite The ion exchange resin was first mixed with about 4 to 8 times its volume of water and stirred at 45 to 65 °C and pH 5.5 to 7.0 for about 30 to 45 minutes using a mechanical stirrer. Then, drotaverine hydrochloride was 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 was prepared with a drug-to-resin ratio of 1:2 to 1:6. The obtained drug-resin complex was filtered and separated through a #80 (ASTM) sieve to obtain a filtered resin complex. Subsequently, the filtered drug-resin complex was washed with water until there was almost no unbound drotaverine drug in the filtrate obtained after washing.

[0083] The obtained drug-resin complex was used directly for the preparation of a suspension. In another experiment, the drug-resin complex was dried overnight at room temperature. The drug-resin complex was dried until it reached a moisture content of less than 5.0% w / w, which was the target moisture content. The dried drug-resin complex was tested for free drotaverine drug. The free drug content should not exceed 2.0%.

[0084] The dried drug-resin complex can be used immediately for the preparation of an oral suspension using appropriate additives or stored for later use. Appropriate additives were added, including, but not limited to, sweeteners, flavoring agents, coloring agents, antioxidants, chelating agents, surfactants, wetting agents, defoaming agents, pH adjusters, acidifying agents, preservatives, co-solvents, and mixtures thereof. See Examples 3 to 11 below.

[0085] After the drug-resin complex formation and any drying process, the drug-resin complex was milled until a target particle size of less than 50 mesh, U.S. Standard Test 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) was achieved.

[0086] Example 2: Method for Preparing a Suspension Formulation from a Drug-Resin Complex The drug-resin complex prepared in Example 1 was used for the production of a suspension formulation product.

[0087] In some embodiments, the method for preparing the stable and delicious suspension formulation of the present disclosure includes the following steps:

[0088] 1. In the initial stage, heat an amount of water corresponding to about 30% of the target batch size to 45 - 65°C and pH 5.5 - 7.0, and then continuously stir and add methylparaben, propylparaben, and crushed sucrose until dissolved to obtain a solution. 2. Cool the solution obtained in step (1) to 25 - 40°C to obtain a cooled solution. 3. Add citric acid and sodium metabisulfite to the cooled solution of step (2) (where citric acid is added first and then sodium metabisulfite), and add them at 500 - 1000 rpm until dissolved to obtain a solution. 4. Add polysorbate 80 to the solution of step (3) at an appropriate 300 - 500 rpm for 15 - 20 minutes to avoid excessive foaming and until fully dispersed to obtain a solution. 5. Immerse xanthan gum or sodium CMC in water corresponding to about 1 - 2% of the target batch size, then add them to the majority of the suspension for a sufficient time, preferably overnight, add the resulting dispersion to the solution obtained in step (4), and then add while stirring until povidone is dissolved to obtain a bulk solution. 6. Sieve the drug - resin complex through a #80 (ASTM) sieve, then add it to the bulk solution of step (5), and stir for 20 - 30 minutes until uniformly dispersed to obtain a bulk suspension. 7. Add simethicone, sorbitol, coloring agent, and flavoring agent to the bulk suspension of step (6) at 1000 - 2000 rpm for 20 - 30 minutes to obtain a suspension product. 8. Adjust the volume of the suspension product of step (7) with an amount of water corresponding to about 5 - 10% of the target batch size to obtain the final suspension product.

[0089] In some embodiments, the final suspension product is manually filled into bottles with a capacity of about 100 - 200 mL, but semi-automatic or fully automatic filling machines may also be used. In some embodiments, the filled bottles are sealed using an ROPP sealing machine.

[0090] Examples of the following formulations containing drotaverine were prepared by varying the ratio of the drug to the resin in the drug - resin complex according to the preparation methods described in Examples 1 and 2 above.

[0091] Example 3: An example of a formulation containing drotaverine was prepared using a drug - resin complex having a ratio of drotaverine to resin of 1:2.5. [Table 1]

[0092] Example 4: An example of a formulation containing drotaverine was prepared using a drug - resin complex having a ratio of drotaverine to resin of 1:3. [Table 2]

[0093] Example 5: An example of a formulation containing drotaverine was prepared using a drug - resin complex having a ratio of drotaverine to resin of 1:4. [Table 3]

[0094] Example 6: An example of a formulation of drotaverine was prepared using a drug - resin complex having a ratio of drotaverine to resin of 1:4. [Table 4]

[0095] Example 7: An example of a formulation of drotaverine was prepared using a drug - resin complex having a ratio of drotaverine to resin of 1:4.

Table 5

[0096] Example 8: Using a drug-resin complex having a ratio of drotaverine to resin of 1:5, an example of a formulation of drotaverine was prepared.

Table 6

[0097] Example 9: Using a drug-resin complex having a ratio of drotaverine to resin of 1:2, an example of a formulation of drotaverine was prepared.

Table 7

[0098] Example 10: Using a drug-resin complex having a ratio of drotaverine to resin of 1:3, an example of a formulation of drotaverine was prepared.

Table 8

[0099] Example 11: Using a drug-resin complex having a ratio of drotaverine to resin of 1:4, an example of a formulation of drotaverine was prepared.

Table 9

[0100] Example 12: The oral suspension (20 mg / mL) formulations described in Examples 3 to 11. One of the representative formulations (Example 8) was evaluated in an in vitro drug dissolution test according to the following test conditions and was proven to have a faster drug release compared to the currently commercially available 20 mg / 5 mL oral suspension product. Therefore, it is suggested that the suspensions disclosed according to these examples have a fast drug release and a faster pain relief than the currently available oral suspension products.

Table 10

[0101] Example 13: Stability Data The disclosed suspension formulations of the listed examples have demonstrated good chemical and physical stability from the perspective of accelerated stability data using the ICH guidelines (40°C ± 2°C / 75% RH ± 5% RH). The impurity levels observed in the resulting products were within the impurity target limits of the ICH guidelines. For one of the representative formulations using the drug-resin complex, the accelerated stability data are shown below (Table 11) in comparison with the formulation (Table 12) manufactured without using the resin complex technology. [Table 11] [Table 12]

[0102] As is evident from the data in Tables 11 and 12, the drug-resin formulation surprisingly and unexpectedly improved the stability of drotaverine. The drug-resin formulation showed low impurity levels in the accelerated stability test.

[0103] In this specification, the subject matter of the present invention has been described with reference to its specific preferred embodiments, but other embodiments are also possible. For illustrative purposes, some embodiments of the present disclosure are in an oral liquid form (suspension, solution, emulsion, elixir, linctus, mixture, etc.) and contain drotaverine or a salt thereof as an antispasmodic agent. Further, 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 understand that the scope of the present disclosure may extend to other combinations and formulations suitable for other age groups, other oral dosage forms, and other antispasmodic agents known in the art.

Claims

1. An oral suspension containing dorotaberine or a salt thereof, wherein the concentration of dorotaberine or a salt thereof exceeds 4 mg / mL.

2. The oral suspension according to claim 1, wherein the liquid oral dosage form contains a dorotaberin-resin complex, and the ratio of dorotaberin to resin is 1:2 to 1:

6.

3. The oral suspension according to claim 2, wherein the dorotaberin-resin composite comprises granules, the size of which is in the range of 150 microns to 300 microns.

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

5. The oral suspension according to claim 1, wherein the dosage form further comprises an antiflatulent agent.

6. The oral suspension according to claim 5, wherein the antiflatulent agent is simethicone or activated dimethicone.

7. The liquid oral suspension according to claim 1, wherein the dorotaberine is a hydrochloride salt.

8. The oral suspension according to claim 1, wherein the dosage form contains 5 to 30 mg / mL of dorotaberine or a salt thereof.

9. The oral suspension according to claim 1, wherein the dosage form contains simethicone or activated dimethicone in an amount of 10 to 80 mg / mL.

10. The oral suspension according to claim 1, wherein the dosage form contains a water-soluble polymer.

11. The oral suspension according to claim 10, wherein the water-soluble polymer comprises hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, soluble starch, or a combination thereof.

12. The oral suspension according to claim 1, wherein the suspension comprises a solvent, and the solvent comprises a sugar alcohol, a polyhydric alcohol, or a combination thereof.

13. The oral suspension according to claim 12, wherein the solvent comprises a sugar alcohol, and the sugar alcohol is sorbitol or sorbitol (70% liquid).

14. The oral suspension according to claim 12, wherein the solvent comprises a polyhydric alcohol, and the polyhydric alcohol is glycerin.

15. The oral suspension according to claim 12, wherein the solvent contains sorbitol (70% liquid) and glycerin in a ratio of 1:1 to 9:

1.

16. The oral suspension according to claim 15, wherein the ratio of sorbitol (70% liquid) to glycerin is 2:1 to 8:

1.

17. The oral suspension according to claim 1, wherein the suspension comprises a suspending agent, wherein the suspending agent comprises sodium carboxymethylcellulose (Sod CMC), xanthan gum, or a combination thereof.

18. The oral suspension according to claim 17, wherein the suspending agent is present in an amount of 0.05% to 3.0% w / w.

19. The oral suspension according to claim 1, wherein the dosage form contains a sweetener.

20. The oral suspension according to claim 19, wherein the sweetener is an artificial sweetener comprising aspartame, sodium saccharin, acesulfame K, sucralose, or a combination thereof.

21. The oral suspension according to claim 19, wherein the sweetener is a natural sweetener comprising sucrose, sorbitol, or a combination thereof.

22. The oral suspension according to claim 1, wherein the dosage form comprises a flavoring agent, a coloring agent, an antioxidant, a chelating agent, a surfactant, a wetting agent, a pH adjuster, an acidifying agent, a preservative, a solvent, or a combination thereof.

23. The oral suspension according to claim 22, wherein the antioxidant is present in an amount of 0.05% to 4% w / w.

24. The oral suspension according to claim 1, wherein the dosage form exhibits dose uniformity, uniform dispersion, and redispersibility when measured by high-performance liquid chromatography.

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

3.

26. The oral suspension according to claim 1, wherein the dosage form is stable for three months when stored under accelerated storage conditions of 40°C and 75% RH.

27. The oral suspension according to claim 1, which is stable for three months when stored under long-term storage conditions of 25-30°C and 60-75% RH.

28. The oral suspension according to claim 1, wherein the liquid oral dosage form exhibits an improved taste.

29. The oral suspension according to claim 1, wherein the liquid oral dosage form exhibits an improved aftertaste.

30. The oral suspension according to claim 1, which exhibits improved taste in a liquid oral dosage form.

31. A method for preparing an oral suspension of dorotaberine or a salt thereof, comprising the following steps: a. A process of heating a certain amount of water, adding at least one type of preservative and crushed sucrose, and continuously stirring the resulting mixture until it is dissolved to obtain a solution; b. A step of cooling the solution to obtain a cooled solution; c. A step of adding at least one acidifying agent and at least one antioxidant to the cooling solution until dissolved to obtain a solution; d. A step of adding at least one wetting agent to the solution until it is dissolved to obtain a solution; e. A step of adding a dispersion obtained by immersing at least one stabilizer and at least one suspension agent in water until dissolved to obtain a bulk solution; f. The drug-resin complex containing dorotaberin or a salt thereof is sieved and separated, the bulk solution obtained in step (e) is added, and the mixture is stirred until dissolved to obtain a bulk suspension; and g. A step of adding a certain amount of water to the bulk suspension to obtain a suspension of dorotaberin or a salt thereof.

32. The method according to claim 31, further comprising the step of adding simethicone or activated dimethicone together with dorotaberine in step (f).

33. The method according to claim 31 or 32, wherein the drug-resin composite comprises Chiron 114, Chiron 314, Indion 204, Indion 234, or Indion 294, or a combination thereof.

34. The method according to claim 31 or 32, wherein the drug-resin complex containing dorotaberin or a salt thereof is mixed in a ratio of 1:2 to 1:

6.

35. The method according to claim 31 or 32, wherein the drug-resin composite is air-dried or dried using a drying apparatus.

36. The method according to claim 31 or 32, wherein the dried drug-resin composite contains less than 5.0% w / w of water.

37. The method according to claim 31 or 32, wherein the sieve used in step (f) includes a mesh, and the mesh is 300 microns or less.

38. An oral suspension according to claim 1 or 2 for treating abdominal pain.