Orally Disintegrating Taste-Enhanced Preparation of Drotaverine and Method for Preparing the Same

Abstract

The present disclosure provides an orally acceptable orally disintegrating tablet formulation of drotaverine or a salt thereof, a method for preparing the same, and their use in therapy.

Description

Technical Field

[0001] The present disclosure relates to an orally palatable formulation of drotaverine or a salt thereof. The present disclosure also relates to an orally palatable formulation of drotaverine or a salt thereof in the form of an orally disintegrating tablet (ODT), an orally dissolving tablet, a dispersible granule, a dispersible tablet, and the like. The present disclosure also relates to a method for preparing such a formulation and its use.

Background Art

[0002] Oral administration of drugs is non-invasive and has a low risk of pain, so it is preferred by patients and leads to improved patient compliance. However, patient groups such as the elderly, children, the intellectually disabled, uncooperative patients, patients with nausea, patients with reduced water intake or food intake, patients who cannot drink water immediately, patients with Parkinson's disease, Alzheimer's disease, patients suffering from dysphagia, postoperative patients who have difficulty sitting, and patients whose water intake is restricted before surgery have difficulty swallowing oral dosage forms. There are also cases where it is difficult to swallow conventional tablets, such as motion sickness, sudden allergic attacks, and coughing. Dysphagia and swallowing disorders are thought to afflict nearly 35% of the general population. Therefore, orally disintegrating tablets (ODTs) are highly desirable in medicine because dosage forms containing active pharmaceutical ingredients do not require water, usually disintegrate rapidly within a few seconds, and can provide optimal convenience to patients.

[0003] ODTs are also called orally dissolving tablets (MDTs), orally dispersible tablets, fast-disintegrating tablets, quick-disintegrating tablets, fast-dissolving tablets, rapid-dissolving tablets, porous tablets, fast-dissolving tablets, and rapid-dissolving tablets. These terms can be used interchangeably, but the term for this dosage form approved by the United States Pharmacopeia (USP) is orally disintegrating tablet or ODT (Guidance for Industry: Orally Disintegrating Tablets, 2008). In some embodiments, ODTs provide the advantages of solid and liquid dosage forms along with the following additional non-limiting special advantages: ●Accurate dosing: Since ODT is a unit solid preparation, it has advantages such as accurate dosing, ease of manufacture, small packaging size, and ease of handling by patients. ●Rapid action: Due to the rapid disintegration of ODT, the drug dissolves quickly and is absorbed rapidly. ●Improved bioavailability: ODT enhances the bioavailability of the active drug because the drug absorbed from saliva in the oral cavity migrates to the stomach, resulting in improved efficacy and enhanced patient compliance. ●Easy administration: ODT preparations are suitable for children, the elderly, inpatients, especially those with intellectual disabilities, psychiatric patients, physically disabled patients, bedridden patients, patients without access to water, and patients during travel, etc. ●ODT combines the advantages of a solid preparation that is particularly easy to handle and a liquid preparation such as ease of swallowing and pre-gastric absorption. ●No sense of obstruction: Since ODT has no risk of airway asphyxiation due to physical obstruction during swallowing, safety and compliance are improved.

[0004] One of the major constraints in the formulation of ODT is the insufficient mechanical strength of the tablets. ODT has a porous and soft forming matrix, and it is compressed into tablets with low pressure, resulting in fragile tablets that are difficult to handle.

[0005] An ideal ODT should exhibit the characteristic of rapid disintegration in the oral cavity and should have sufficient physical strength (i.e., hardness) to maintain physical integrity even at the stage of patient handling, such as when taking the tablets out of manufacturing, distribution, and packaging.

[0006] Taste is another important parameter for orally administered drugs. Drugs with unpleasant or bitter tastes pose a major challenge for formulation scientists in developing palatable orally disintegrating tablets. Furthermore, the presence of large particles of disintegrating tablets that do not dissolve in saliva or dissolve slowly may leave an unpleasant gritty feeling or unpleasant aftertaste, so it is advantageous for ODT to have minimal or no oral residues.

[0007] Drotaverine hydrochloride is a benzylisoquinoline derivative and an analogue of papaverine. Drotaverine is a very potent antispasmodic. The mechanism of action and pharmacokinetic parameters of drotaverine are well known in relation to the diseases, disorders or physiological states in which drotaverine is used. Drotaverine is known to effectively contribute to the treatment of painful spasms in various diseases, either alone or in combination, and is a drug of choice in emergency medicine. Drotaverine has no side effects such as those of anticholinergic drugs and does not mask the symptoms of "acute abdomen".

[0008] Abdominal pain is a common complaint in both adults and children. Drotaverine is an effective and safe drug for the management of recurrent abdominal pain in children. It is also used as an off-label drug for gastrointestinal disorders in preschool and school-age children. In the treatment of acute symptoms, it is desirable for a pharmaceutical composition to have rapid and stable onset of action and good bioavailability. Currently marketed drotaverine injection provides rapid absorption by parenteral injection, so it is suitable for such acute cases. However, for many patients, especially in emergency situations or during travel when medical staff are not accessible, it is not desirable. In such scenarios, ODTs are a suitable alternative.

[0009] Currently, in addition to the injection form, drotaverine is also sold as a conventional immediate-release (IR) formulation such as IR film-coated tablets and syrups. There are 40mg and 80mg tablets of drotaverine, and the prescribed dose is 120 - 240mg / day. The available drotaverine IR film-coated tablets usually require water for oral administration, so they are not suitable for some patient groups.

[0010] Drotaverine is a very bitter drug with an aftertaste. There are effective approaches to masking the taste of bitter drugs, but it is known that an approach effective for one drug is often not applicable to another drug.

[0011] Moreover, drotaverine is susceptible to oxidation and the influence of pH, and is chemically unstable. To mask the taste of drotaverine hydrochloride, many techniques have been studied so far, such as solid dispersion, pharmaceutical coating, and complexation with polymers or resins. However, there is no literature report on successful formulation of a chemically stable and highly palatable ODT formulation of drotaverine. Therefore, it is necessary to treat patients who cannot swallow or do not want to swallow currently available drotaverine formulations.

[0012] Currently available techniques for manufacturing ODT formulations include, in addition to the conventional wet granulation process, the use of freeze-drying, cotton candy, sublimation, melt extrusion, and direct compression. Among various manufacturing processes, direct tableting is one of the most economical methods because it uses conventional equipment, commercially available excipients, and a relatively simple process. However, the disintegration ability of ODTs manufactured by direct tableting is usually limited by the size and hardness of the obtained tablets. Therefore, in order to develop a dosage form with high disintegration ability, it is generally necessary to use excipients that provide both cohesiveness for compression and disintegration when the dosage form comes into contact with saliva in the oral cavity.

[0013] US20090136569A1 discloses an orally disintegrating tablet containing three components: 1) granules containing bespotastine besilate in which the bitterness of the drug is not suppressed; 2) granules containing water-soluble saccharides and a binder; 3) an excipient containing a flavor component, a sweetening agent, and a lubricant. However, the tablet manufacturing process is long, the production efficiency is poor, and it is troubled by a decrease in content uniformity due to granule classification.

[0014] US20060172005A1 discloses a tablet that rapidly disintegrates in the oral cavity and contains an active ingredient and 70% by mass or more of cyclodextrin or a derivative thereof. However, such tablets have a problem of poor texture because they contain a large amount of cyclodextrin. Furthermore, since cyclodextrin has high hygroscopicity, it may affect the hardness of the tablets during storage.

[0015] US20090311321A1 discloses a taste-masking ODT of mitiglinide calcium comprising microcrystalline cellulose, at least one masking agent, a sugar or sugar alcohol, and at least one member selected from corn starch and partially pre-gelatinized starch.

[0016] US7510728B2 discloses a fast-disintegrating solid pharmaceutical formulation of pioglitazone hydrochloride.

[0017] EP2808013A1 discloses an ODT produced by compressing a mixture of avanafil, nicergoline, imidapril hydrochloride, bisoprolol fumarate, taltrimeline hydrate, and allopurinol.

[0018] Despite previous efforts, none of the known technologies have been able to overcome the drawbacks of drotaverine to provide a chemically stable and palatable oral formulation suitable for ODT. Therefore, it is necessary to develop a chemically stable and palatable ODT of drotaverine or its salts to improve high acceptability, rapid onset of action for early pain relief, and convenience for patients with dysphagia. Furthermore, such a formulation should be easily prepared by processes such as direct compression, dry granulation, or wet granulation processes. Additionally, in some embodiments, the size of the ODT should be made as small as possible so that minimal residue remains or no residue remains after disintegration in the oral cavity. In some embodiments, since water is not used to swallow the ODT, it is desirable that the tablet disintegrates in the oral cavity, preferably within less than 30 seconds, upon contact with saliva.

Summary of the Invention

[0019] The present disclosure relates to an orally disintegrating tablet (ODT) containing drotaverine or a pharmaceutical salt thereof that disintegrates in saliva and is swallowed without the need for water. These disclosed formulations offer significant advantages, particularly to elderly patients who typically have difficulty swallowing such tablets, compared to currently marketed conventional film-coated swallowable tablets. The disclosed pharmaceutical compositions are chemically stable throughout the shelf life of the product. By using a novel manufacturing process, the disclosed formulations exhibit improved taste, improved aftertaste, and improved mouthfeel.

[0020] In some embodiments, the present disclosure provides an oral dosage form comprising drotaverine or a salt thereof and an ion exchange resin, wherein the drotaverine and the ion exchange resin form a drotaverine-resin exchange complex and the dosage form is formulated as an orally disintegrating tablet. In some embodiments, the present disclosure provides an oral dosage form comprising drotaverine or a salt thereof and a flavor enhancer. In some embodiments, the dosage form comprises a bitterness masking flavor. In some embodiments, the dosage form comprises 2.5 to 100 mg of drotaverine or a salt thereof. In some embodiments, the dosage form comprises 10 to 100 mg of drotaverine or a salt thereof. In some embodiments, the dosage form comprises drotaverine hydrochloride. In some embodiments, the ion exchange resin is Kyron 114, Kyron 314, Indion 204, Indion 234, Indion 294, or a combination thereof. In some embodiments, the ratio of drotaverine to the ion exchange resin is 1:2 to 1:6. In some embodiments, the oral dosage form is in the form of granules, and the size of the granules ranges from about 850 microns to 300 microns. In some embodiments, the dosage form has a hardness of 3 to 12 kp. The oral dosage form according to any one of claims 1 to 4, wherein in some embodiments, the dosage form disintegrates in the mouth within 60 seconds without water. In some embodiments, the dosage form disintegrates in the mouth within 30 seconds without water. In some embodiments, the dosage form disintegrates in 1 to 3 mL of water within 60 seconds. In some embodiments, the dosage form disintegrates in 1 to 3 mL of water within 30 seconds.

[0021] In some embodiments, the dosage form further comprises a diluent, a disintegrant, a flavoring agent, a sweetening agent, a lubricant, an anti-adherent, or a combination thereof. In some embodiments, the excipient-to-drug-resin complex ratio is from 0.05:1 to 2.5:1. In some embodiments, the excipient-to-drug-resin complex ratio is from 0.1:1 to 2:1.

[0022] In some embodiments, the dosage form further comprises at least one diluent, and the diluent comprises a monosaccharide, an oligosaccharide, a polysaccharide, lactose, a sugar alcohol, cellulose powder, microcrystalline cellulose, siliconized microcrystalline cellulose, a derivative of chemically modified cellulose, starch, or a combination thereof.

[0023] In some embodiments, the dosage form further comprises at least one disintegrant, and the disintegrant comprises at least one of starch, natural or chemically modified cellulose, microcrystalline cellulose, gum, alginic acid or its salts, sugar, aluminum oxide, or a synthetic polymer. In some embodiments, the disintegrant is in an amount of 1% to 10% w / w. In some embodiments, the disintegrant is in an amount of 2% to 8% w / w.

[0024] In some embodiments, the dosage form further comprises at least one flavoring agent, and the flavoring agent comprises a strawberry flavor, a cherry flavor, an orange flavor, a peppermint flavor, a blackcurrant flavor, a banana flavor, a raspberry flavor, a red fruit flavor, a wild berry flavor, a caramel flavor, or a combination thereof.

[0025] In some embodiments, the dosage form further comprises at least one sweetening agent, where the sweetening agent comprises aspartame, acesulfame potassium, sodium saccharin, neohesperidin dihydrochalcone, sucralose, sucrose, fructose, monoammonium glycyrrhizinate, or a combination thereof.

[0026] In some embodiments, the dosage form further comprises at least one lubricant, and the lubricant comprises sodium benzoate, sodium stearyl fumarate, calcium stearate, magnesium stearate, zinc stearate, glyceryl behenate, stearic acid, glyceryl monostearate, or combinations thereof.

[0027] In some embodiments, the present disclosure provides an oral dosage form comprising drotaverine or a salt thereof and an ion exchange resin, wherein the oral dosage form is stable for 3 months when stored under long-term storage conditions of 25-30 °C and 60-75% relative humidity (RH). In some embodiments, the dosage form is stable for 6 months when stored under long-term storage conditions of 25-30 °C and 60-75% RH. In some embodiments, the dosage form is stable for 2 years when stored under long-term storage conditions of 25-30 °C and 60-75% RH. In some embodiments, the dosage form is stable for 3 months when stored under accelerated storage conditions of 40 °C and 75% RH. In some embodiments, the dosage form is stable for 6 months when stored under accelerated storage conditions of 40 °C and 75% RH. In some embodiments, the oral dosage form exhibits an improved taste. In some embodiments, the oral dosage form exhibits an improved aftertaste. In some embodiments, the oral dosage form exhibits an improved palatability.

[0028] In some embodiments, the present disclosure provides a method for preparing an orally disintegrating tablet of drotaverine or a salt thereof, comprising: (a) mixing an ion exchange resin with water; (b) adding drotaverine or a salt thereof to the ion exchange resin mixture to form a drug-resin complex; (c) drying the drug-resin complex to form a dried drug-resin complex; (d) sieving the dried drug-resin complex to obtain drug-resin complex granules; (e) separately obtaining and weighing the drug-resin complex granules and at least one excipient; (f) passing the drug-resin complex granules and the excipient through a mesh; (g) mixing the drug-resin complex granules and the excipient; and (h) forming the mixed drug-resin complex granules and the excipient into an orally disintegrating tablet. In some embodiments, the ion exchange resin includes Kyron 114, Kyron 314, Indion 204, Indion 234, Indion 294. In some embodiments, the ion exchange resin is mixed with water for 30 to 45 minutes, then drotaverine is slowly added and mixed for at least 2 to 4 hours. In some embodiments, the ion exchange resin and drotaverine or a salt thereof are mixed at a ratio of 2:1 to 6:1. 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 dried drug-resin complex is sieved through a mesh, and the mesh is 850 microns or less. In some embodiments, the drug-resin complex granules and the excipient are mixed for 10 to 20 minutes. In some embodiments, the orally disintegrating tablet is formed using direct compression, dry granulation, wet granulation, or fluidized bed preparation methods. In some embodiments, at least 90% of the orally disintegrating tablet dissolves in vitro in 5 minutes using a paddle at 40 RPM in a 0.1N HCl dissolution medium.

[0029] In some embodiments, the present disclosure provides a method for treating abdominal pain, comprising administering an oral dosage form comprising drotaverine or a salt thereof to a subject in need thereof, wherein the oral dosage form comprises any of claims 1-24.

[0030] In some embodiments, the present disclosure provides the use of an oral dosage form comprising drotaverine or a salt thereof for treating abdominal pain, which comprises administering the oral dosage form to a subject in need thereof, wherein the oral dosage form comprises any one of claims 1 to 24.

Mode for Carrying Out the Invention

[0031] The bitterness of pharmaceuticals is a point to be considered in patient compliance. Oral administration of bitter pharmaceuticals can be inhibited by their unpleasant taste, leading to non-compliance or the patient's inability to swallow the drug, thereby worsening the medical condition. The present disclosure relates to an ODT comprising drotaverine or a pharmaceutical salt thereof.

[0032] In some embodiments, the present disclosure provides a palatable ODT formulation of an antispasmodic agent, particularly drotaverine or a salt thereof, that rapidly disintegrates in the oral cavity, particularly in less than 30 seconds.

[0033] In some embodiments, the present disclosure provides ODT formulations of drotaverine or a salt thereof in multiple strengths. In some embodiments, these formulations provide a flexible dosage range suitable for different patient groups. In some embodiments, the present disclosure provides a method for preparing a palatable ODT formulation of drotaverine or a salt thereof. In some embodiments, the present disclosure provides the use of an oral formulation

[0034] In some embodiments, the ODT formulations of the present disclosure have sufficient mechanical resistance to withstand crumbling or breaking during manufacturing and distribution operations, unlike oral lyophilized products, saccharide-based chewable tablets, and other rapidly disintegrating formulations such as wafers.

[0035] In some embodiments, the ODT formulations of the present disclosure exhibit chemical stability through long-term storage conditions.

[0036] In some embodiments, the present disclosure provides an orally disintegrating tablet (ODT) of drotaverine that exhibits improved taste, aftertaste, and palatability. The term "taste" is used herein to refer to the flavor sensation experienced when a subject's tongue contacts the dosage form. The term "aftertaste" is used herein to refer to the flavor sensation experienced in the oral cavity after administration of the dosage form. For example, the aftertaste typically persists well after administration of drotaverine. This term is used herein to refer to the physical sensation when the dosage form is in the subject's mouth, e.g., the texture of the dosage form. In some embodiments, the ODTs disclosed herein exhibit improved taste, aftertaste, and palatability compared to currently available drotaverine tablets.

[0037] The terms "stable", "stability" or "stabilization" mean that the dosage form can maintain product performance test parameters such as the amount of ingredients and the amount of related substances without significant change from the initial level.

[0038] The term "significant change" means a change of 5% or more from the initial result. For example, if the initial amount of a component is 98%, a significant change means that the amount of that component becomes 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. In some embodiments, the ODT is stable for 3 months under long-term storage conditions. In some embodiments, the ODT is stable for 6 months under long-term storage conditions. In some embodiments, the long-term storage conditions are 15 - 30°C, 60 - 75% RH. In some embodiments, the long-term storage conditions include 25 - 30°C at 60 - 75% RH.

[0039] In some embodiments, the ODT formulations disclosed in the present disclosure are suitable for all age groups, including but not limited to the elderly, children, the intellectually disabled, uncooperative patients, patients who experience nausea, patients with reduced fluid or food intake, patients who do not have immediate access to water, patients suffering from Parkinson's disease, Alzheimer's disease, dysphagia, postoperative patients who have difficulty sitting, or patients whose access to water is restricted prior to surgery, who have difficulty swallowing oral dosage forms.

[0040] In some embodiments, the ODT formulations of the present disclosure mask the bitter taste of drotaverine. During the development of the palatable ODT formulations of the present disclosure, various methods and combination approaches have been attempted to overcome the sensory challenges of the bitter taste and aftertaste of drotaverine, including the approach of ion exchange resins.

[0041] In the ion exchange resin approach, although the strong unpleasant bitter taste remaining in the aftertaste of drotaverine was masked, the resulting products did not achieve acceptable palatability characteristics. For example, the resulting products were gritty and contained bulky residues after administration. To address these problems, further experiments were conducted. As a result, an ODT formulation with a desirable texture was developed with an appropriate particle size and an appropriate ratio of drug-resin complex. Finally, a combination of ion exchange resin, excipient, and flavor mixture resulted in a palatable ODT formulation of drotaverine. The developed ODT formulations of the present disclosure can keep the tablet size small and reduce the amount of oral residues after disintegration because the excipient is minimal. As a result, the ODT of the present disclosure has a pleasant mouthfeel.

[0042] Ion exchange resin technology can be used for taste masking, and surprisingly, the developed formulations also improve chemical stability.

[0043] In some embodiments, the ODT of the present disclosure rapidly disintegrates within less than 30 seconds in the oral cavity without water. In some embodiments, the developed ODT provides content uniformity and strength of the compressed tablets and reliably delivers intact tablets to the patient until administration. In some embodiments, the ODT formulation of the present disclosure provides rapid release of drotaverine and provides rapid analgesia to the patient. In certain embodiments, the ODT formulation of the present disclosure does not adversely affect the elution and release of the drug despite using ion exchange resin complexation technology. In some embodiments, the ODT formulation of the present disclosure is prepared by a cost-effective and easily scalable manufacturing process.

[0044] In some embodiments, the ODT formulation of the present disclosure contains components commonly used in the pharmaceutical industry, which are referred to herein as conventional excipients, but are not limited to diluents, binders, disintegrants, flavors, sweeteners, lubricants, glidants, anti-adhesion agents, and mixtures thereof.

[0045] Examples of diluents include saccharides such as monosaccharides, oligosaccharides, polysaccharides, lactose in various forms, anhydrous, monohydrate, mannitol, maltitol, sorbitol, maltitol, xylitol, isomalt, erythritol and other sugar alcohols, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, chemically modified cellulose derivatives such as hydroxypropyl cellulose, isomalt and erythritol, cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, or derivatives of chemically modified cellulose, such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, starches in various forms, such as corn, maize, potato, etc. For example, starches of corn, maize, potato, sucrose, or mixtures thereof, etc. may be mentioned.

[0046] As used herein, the term "disintegrant" refers to a compound that promotes the fragmentation or disintegration of a tablet when placed in an aqueous medium. Disintegrants swell upon contact with water, changing in volume or form to generate a disruptive force that breaks apart the compressed tablet. Examples of disintegrants include natural starches such as corn starch and potato starch, directly compressible starches such as starch 1500, modified or pregelatinized starches such as carboxymethyl starch and sodium starch glycolate; natural or chemically modified celluloses, particularly cross-linked sodium carboxymethyl cellulose (croscarmellose sodium) or low-substituted hydroxypropyl cellulose; microcrystalline cellulose, gums, particularly agar gum and guar gum; alginic acid or its salts; acetates and citrates, sugars (particularly lactose, mannitol and sorbitol), aluminum oxide, and synthetic polymers such as crospovidone. In some embodiments, the disintegrant is in an amount of 1% to 10% w / w. In some embodiments, the disintegrant is in an amount of 2% to 8% w / w.

[0047] In some embodiments, the ODT formulation of the present invention comprises a binder. In some embodiments, the binder is starch, polyvinylpyrrolidone, natural gum, synthetic gum, a cellulose-based polymer, or a combination thereof.

[0048] In some embodiments, the ODT formulation of the present invention comprises a lubricant, a glidant, or a combination thereof. In some embodiments, the lubricant and glidant are talc, colloidal silicon dioxide, stearic acid, sodium stearyl fumarate, magnesium stearate, or a combination thereof.

[0049] Examples of suitable flavoring agents used in the formulations of the present disclosure include lemon flavor, anise flavor, cinnamon flavor, chocolate powder flavor, strawberry flavor, cherry flavor, orange flavor, peppermint flavor, blackcurrant flavor, banana flavor, raspberry flavor, red fruit flavor, wild berry flavor, and caramel flavor. In some embodiments, the flavoring agent is used in an amount less than 3.0% by weight.

[0050] Certain flavoring agents are particularly effective in masking the bitter aftertaste of drotaverine. These flavoring agents are referred to as bitter-masking flavors. In some embodiments, the formulations of the present disclosure include a bitter-masking flavor. In some embodiments, the bitter-masking flavor includes peppermint flavor, lemon flavor, anise flavor, cinnamon flavor, chocolate powder flavor, or a combination thereof.

[0051] Examples of suitable sweetening agents used in the formulations of the present disclosure include aspartame, acesulfame potassium, sodium saccharin, neohesperidin dihydrochalcone, sucralose, sucrose, fructose, monoammonium glycyrrhizinate, licorice powder, cinnamon powder, or a combination thereof. In some embodiments, the sweetening agent is used in an amount of about 1.0 to 4.0% by weight.

[0052] Certain sweetening agents are particularly effective in masking the bitter aftertaste of drotaverine. These sweetening agents are referred to as taste enhancers. In some embodiments, the formulations of the present disclosure include a taste enhancer. In some embodiments, the taste enhancer includes licorice powder, cinnamon powder, monoammonium glycyrrhizinate (MAG), or a combination thereof.

[0053] In some embodiments, the lubricants used herein are additional excipients that can affect the performance of the orally dispersible pharmaceutical formulation. Suitable examples of lubricants include sodium benzoate, sodium stearyl fumarate, calcium stearate, magnesium stearate, zinc stearate, glyceryl behenate, stearic acid, and glyceryl monostearate. In some embodiments, the lubricant for the formulations of the present disclosure is sodium stearyl fumarate or magnesium stearate or a combination thereof. In some embodiments, the lubricant is used in an amount of about 0.25 to 5% by weight.

[0054] The development of the ODTs of the present disclosure will be briefly described below.

[0055] In the initial studies of the development of the present disclosure, several experiments were conducted on combinations of diluents, sweeteners, flavoring agents, and drotaverine hydrochloride. The manufacturing processes tried were direct compression, dry granulation, wet granulation using high-shear granulation, and the fluidized bed process method. Some formulations were able to achieve rapid disintegration of the tablets in the initial stage of development, but the desired mouthfeel could not be obtained in the final product. Furthermore, the high impurity levels observed in the final tablets exceeded the limits recommended by the ICH (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use) guidelines. Additionally, the bitterness caused by drotaverine could not be masked by these conventional methods or the combined use of flavoring agents and sweeteners.

[0056] To mask the bitterness of drotaverine, an approach using ion exchange resins has been attempted. Ion exchange resins are high molecular weight polyelectrolytes that can exchange mobile ions with the same charge with the surrounding medium. Ion exchange resins are insoluble matrices (or support structures), usually small (1 - 2 mm in diameter) beads in white or yellowish color, and are made from organic polymer substrates. This material has a highly developed pore structure on the surface, which serves as a site where ions are easily captured and released. Since the capture of ions occurs simultaneously with the release of other ions, this process is called ion exchange. There are multiple different types of ion exchange resins manufactured to selectively prefer one or more different types of ions. In some embodiments, suitable ion exchange resins used herein are cross-linked polyacrylic acid polymers and their salts, such as Kyron grades (Kyron 114, Kyron 314), resin grades of the Indion series (Indion 204, Indion 234, Indion 294), and the like.

[0057] Ion exchange resins are known as polymeric materials that have the potential to form weak bonds with positively charged drugs. Ion exchange resins are insoluble polymers with acidic or basic functional groups and have the ability to exchange counterions with the surrounding aqueous solution. The complex formation between the drug and the ion exchange resin is based on the drug loading ratio (the ratio of the active ingredient to the resin), temperature, and pH. In some embodiments, an acidic or basic ionizable active ingredient is dissolved or dispersed in water and mixed with a suitable ion exchange resin to load the active ingredient onto the ion exchange resin.

[0058] A diagram of the ion exchange process showing the acid-base complex formed from a positively charged drug (D+) and an ion exchange resin (RCOO-) is shown below: D + +RCOO - →RCOO-D (oral formulation) RCOO-D + H + +Cl - →D + +RCOOH + Cl - (The formulation is in the stomach)

[0059] The ion exchange resin masks the taste of the drug because the formed resin-drug complex hardly elutes the drug at a pH close to neutral in the oral cavity. Therefore, the taste of the drug is masked in the oral cavity without inhibiting the drug release profile in the stomach.

[0060] In order to develop a suitable drotaverine drug-resin complex that masks bitterness and aftertaste, several experiments were conducted. The drug and an appropriate grade of ion exchange resin were selected based on initial research, and the drug-to-polymer ratio was used in the range of 1:1 to 1:8.

[0061] First, the ion exchange resin was mixed in water and stirred for a sufficient time under appropriate temperature and pH. Then, drotaverine was slowly added to the resin mixture and stirred for a sufficient time to obtain a resinate or drug-resin complex. The obtained resinate was separated by filtration using appropriate means. Then, the filtered drug-resin complex was washed until there was almost no unbound or free drotaverine drug in the filtrate obtained after washing. The free drotaverine drug not bound to the resin should preferably not exceed 2% w / w of the input drug at the start of the complexation process and preferably be less than 1% w / w. Then, the drug-resin complex is air-dried at room temperature overnight or dried using an appropriate drying device under appropriate temperature conditions until the desired moisture content is reached. Examples of drying devices suitable for drying the drug-resin complex include, but are not limited to, tray dryers and fluidized bed dryers, and it can be dried until the target moisture content is less than 5.0% w / w. The dried drug-resin complex is tested for free drotaverine drug. The free drug content must be 2.0% or less.

[0062] The dried drug-resin complex was then used in the formulation of an oral preparation using appropriate pharmaceutical excipients or additives including sweeteners, flavors, colorants, antioxidants, chelating agents, surfactants, wetting agents, defoaming agents, pH adjusters, acidulants, preservatives, co-solvents, and mixtures thereof.

[0063] Based on extensive experiments with various combinations, a drug-resin complex with a ratio of 1:2 to 1:6 was finalized, and after the drug-resin complexation and drying processes, the particle size of the drug-resin complex was finalized. To ensure a smooth texture and palatability, the particle size of the dried drug-resin complex granules was made small enough with appropriate grinding parameters so that the final product was free of jaggedness and a smooth feel was obtained upon swallowing.

[0064] Based on the above extensive research, it was established that an appropriate particle size is below ASTM 20 mesh (equivalent to about 850 microns), preferably ASTM 30 mesh (equivalent to about 600 microns), and more preferably about ASTM 50 mesh (equivalent to about 300 microns).

[0065] After finalizing the desired particle size specifications of the drug-resin complex, further formulation experiments were conducted towards formulating an orally disintegrating tablet. The bitterness of drotaverine was masked at a desirable ratio of drug to resin using an appropriate ion exchange resin, but it was insufficient to obtain a desirable mouthfeel for an orally disintegrating tablet. To obtain desirable pharmaceutical performance parameters along with an acceptable mouthfeel, in addition to using the drug-resin complex as the core material, further development research was conducted to achieve an appropriate ratio of "pharmaceutical excipients". Accordingly, "pharmaceutical excipients" or "additives" as referred to herein were used to formulate an additional, final oral-dissolving tablet product. Pharmaceutical excipients can be selected from diluents, binders, lubricants, disintegrants, colorants, stabilizers, glidants, etc. In some embodiments, the ratio of the pharmaceutical excipient to the drug-resin complex is 0.05:1 to 2.5:1. In some embodiments, the ratio of the pharmaceutical excipient to the drug-resin complex is 0.1:1 to 2:1.

[0066] Additional additives include flavor enhancers, bitterness masking flavors, antioxidants, chelating agents, surfactants, wetting agents, defoaming agents, pH adjusters, acidulants, preservatives, and mixtures thereof.

[0067] In some embodiments, the ODT formulation of the present invention includes an acidifying agent, an acidifying agent, a pH adjuster, or a combination thereof. In some embodiments, the acidifying agent, the acidifying agent, or the pH adjuster is citric acid, fumaric acid, lactic acid, maleic acid, malic acid, tartaric acid, or a combination thereof.

[0068] In some embodiments, the ODT formulation includes 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.

[0069] In some embodiments, the ODT formulation includes a wetting agent. In some embodiments, the wetting agent is a long-chain alkyl sulfonate, a long-chain alkyl 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-chain alkyl 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 the addition of ethylene oxide via polymerization to obtain a sorbitan fatty acid ester. These are nonionic hydrophilic surfactants generally known as Tweens or polysorbates, for example, polysorbate 20, 60, and 80.

[0070] In some embodiments, the ODT contains a preservative. In some embodiments, the preservative is a paraben or its sodium salt. In some embodiments, the parabens are methylparaben, propylparaben, or their sodium salts. In some embodiments, the preservative is benzyl alcohol thiomersal, or a combination thereof.

[0071] The ODT of the present disclosure can be prepared by direct compression, dry granulation, or wet granulation processes. The term "direct compression" as used in the context of the present disclosure defines a process in which tablets are directly compressed from a powder mixture of a drug-resin dry complex and excipients, and this process uniformly flows into the die cavity to form a solid compact. The term "dry granulation" process is used in the context of the present disclosure to define a process for manufacturing the final pharmaceutical product by preparing a free-flowing mixture of granules with an accurate particle size distribution using a slugging or roller compression process, then sizing the slug or compact, and then adding a lubricant before compressing the tablets. The term "wet granulation" includes the agglomeration or combination of fine powder particles using a suitable non-toxic granulating liquid to form larger, stronger, and relatively permanent structures called granules. The drug-resin complex can be granulated as such or together with at least one pharmaceutical excipient for use in the preparation of dosage forms.

[0072] The weight of the compressed tablets can range from 125 mg to 500 mg depending on the appropriate ratios of complexing agent, diluent, disintegrant, lubricant, sweetening agent, and flavor for different strengths of the drotaverine formulations according to the present disclosure.

[0073] In some embodiments, compressed ODTs containing coated resin particles rapidly disintegrate into individual particles in the oral cavity upon contact with saliva. Further, in some embodiments, the drug release rate is not affected by the complexation and compression steps involved in the manufacturing process.

[0074] To achieve a comfortable mouthfeel, the inventors also examined various combinations of diluents and flavor enhancing ingredients to achieve the desired taste. In some embodiments, the selected bulk diluent is water soluble or dispersible and can be combined in a desired ratio with a less water-soluble swelling excipient.

[0075] Examples of commonly used diluents include microcrystalline cellulose, siliconized microcrystalline cellulose, or derivatives of chemically modified cellulose such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, different forms of starch such as corn, maize, potato starch, sucrose, or mixtures thereof.

[0076] The inventors also conducted experiments using water-soluble diluents such as saccharides. Examples of saccharides containing diluents include monosaccharides, oligosaccharides or polysaccharides, various forms of lactose, anhydrous, monohydrate, mannitol, maltitol, sorbitol, maltitol, xylitol, isomalt, sugar alcohols such as erythritol, and powdered cellulose.

[0077] Various grades of powdered and direct compressible grades of sugar alcohols of sorbitol, xylitol and mannitol are commercially available and have the ideal physical and chemical properties to constitute a suitable diluent. In some embodiments, the direct compressibility (DC) grades of sugar alcohols, when used in appropriate amounts, have good fluidity and compressibility properties along with excellent mouthfeel. Examples of DC grade sugar alcohols include Prosolv ODT, Ludiflash, Pharmaburst, F-Melt, etc.

[0078] Extensive research has been conducted to reach an appropriate ratio of sugar alcohol and common diluents such as microcrystalline cellulose (MCC), starch, and lactose, either alone or in combination, as co-processed materials for DC grades, and an appropriate formulation with excellent compressibility that disintegrates in less than 30 seconds, preferably less than 20 seconds, when held in the mouth has been achieved. Furthermore, these selected excipients have good diluting ability due to the particle size and morphology, enabling the incorporation of active ingredients that are difficult to compress and minimizing the size of the final tablet product.

[0079] The flavoring agents used are of the types and amounts desired to enhance the palatability of the formulation. Flavoring agents that can be used in the present disclosure include natural flavors, natural fruit flavors, artificial flavors, artificial fruit flavors, flavor enhancers, or mixtures thereof. Examples of natural flavors, artificial flavors, or mixtures thereof include licorice, mint (such as peppermint or spearmint), and menthol. Examples of natural fruit flavors, artificial fruit flavors, or mixtures thereof include cherry, grape, strawberry, orange, melon, banana, citrus, tutti-frutti, vanilla, and the like. Flavoring agents are generally provided in an amount effective to provide a pleasant taste to the pharmaceutical formulation and as a minor component of the flavoring and deodorizing composition, but the addition of at least one flavoring agent may be used, and in some embodiments, one or more flavoring agents may be employed.

[0080] In some embodiments, the ODT contains a foaming agent that can be added to improve the mouthfeel. In some embodiments, the foaming agent is sodium bicarbonate, citric acid, or a combination thereof. In some embodiments, the flavoring agent or foaming agent is used in addition to other taste masking techniques to achieve the target taste profile of the product.

[0081] In some embodiments, the ODT contains a colorant. The colorant or chromogen can be incorporated to provide an attractive color to the pharmaceutical formulation. In some embodiments, the colorant is considered safe for human consumption by the relevant government regulatory agencies and avoids chemical incompatibility with other ingredients. In some embodiments, the colorant is Sunset Yellow FCF, a synthetic lemon yellow azo dye (known as FD&C Yellow No. 6 and tartrazine in the United States). It is also known as FD&C Yellow 5.

[0082] Based on extensive experiments combining the above diluents with appropriate disintegrants, sweeteners, and flavors, several formulation prototypes were selected, and it was found that the disintegration of the resulting tablets was less than 1 minute, and even less than 20 seconds. The chemical stability of these developed prototypes was evaluated under accelerated stability conditions. As a result, it was confirmed that the impurity concentration in the product meets the ICH impurity criteria.

[0083] The drug-resin complex formulation was evaluated for taste masking. However, surprisingly, a significant improvement in the chemical stability of drotaverine in the drug-resin complex was observed compared to formulations without ion-exchange resin. Furthermore, the developed ODT achieved approximately 90% drug release in about 5 minutes, showing a rapid onset of action.

[0084] The prepared drug-resin complex is employed in the manufacture of ODT. In some embodiments, the method for preparing the ODT of the present disclosure includes the following steps: a. Weigh the required amounts of appropriate ingredients according to various formulations; b. Pass the required materials separately through appropriate sieves; c. Pass the sweetener and granular lubricant separately through appropriate sieves; d. Mix the drug-resin complex with the required diluent in an appropriate manner for a sufficient time; e. Mix the product of step d with an appropriate lubricant by appropriate means for a sufficient time.

[0085] To measure the compression of the ODT, a die punch tool was used. The hardness of the prepared tablets was about 3 - 12 kp, and the disintegration time was less than 1 minute, preferably 10 - 30 seconds.

[0086] In summary, the present disclosure provides an orally disintegrating taste-masked pharmaceutical formulation comprising chemically stabilized drotaverine, which does not require water for oral administration and disintegrates in the oral cavity preferably within less than 30 seconds upon contact with saliva. In some embodiments, the drug release rate of the drug-resin formulation of the present disclosure is faster than that of currently marketed film-coated tablets, which leads to faster action and improved absorption.

[0087] The following non-limiting examples are provided as representative suitable ODT formulations that meet the objectives, features, and advantages of the present disclosure.

Example

[0088] Example 1: Method for preparing a drug-resin complex The ion exchange resin was first mixed with 4 - 8 volumes of water and stirred for about 30 - 45 minutes using a mechanical stirrer. Then, drotaverine hydrochloride was slowly added to the resin mixture and stirred for at least 2 - 4 hours to obtain a drug-resin complex. The drug-resin complex was prepared using the drug and resin in a ratio of 1:2 to 1:6. The obtained drug-resin complex was separated by filtration using a 30# sieve (ASTM) to obtain a filtered drug-resin complex. In some embodiments, a 50# sieve can be used. Then, the filtered drug-resin complex was washed with water until there was little unbound drotaverine drug remaining in the filtrate obtained after washing.

[0089] The obtained drug-resin complex was air-dried overnight at room temperature or dried at 50 - 70 °C using a fluid bed dryer. The drying of the drug-resin complex was carried out until the water content was less than 5.0% w / w. The dried drug-resin complex was tested for unbound drotaverine drug. The unbound drotaverine drug content should be 2.0% or less.

[0090] The dried drug-resin complex can be used immediately for the formulation of ODT or stored for later use. For the formulation of ODT, the excipients described in Examples 3 to 18 below were added to the dry drug-resin complex as described in Example 2 below.

[0091] Before mixing the dry drug-resin complex with the excipient, the particle size of the dry drug-resin complex was reduced using a pulverizer. A multi-mill or a vibrating granulator can be used. Suitable particle sizes are 20 mesh, ASTM (American Standard Test Sieve Series) (corresponding to about 850 microns), 30 mesh, ASTM (corresponding to about 600 microns) or 50 mesh, ASTM (corresponding to about 300 microns) or less.

[0092] Once the desired particle size specification of the drug-resin complex was determined, further formulation experiments were conducted to prepare orally disintegrating tablets as described in Example 2.

[0093] Example 2: Method for Preparing Orally Disintegrating Tablets from a Drug-Resin Complex The drug-resin complex prepared in Example 1 was used for the production of ODT. It is as follows: a. Weigh separately the drug-resin granules and the excipient described in Examples 3 - 18 below; b. Pass the drug-resin granules and the excipient (excluding sweeteners, flavors, lubricants) separately through a #45 sieve (ASTM); c. Pass the sweetener, flavor, and granular lubricant separately through a #60 sieve (ASTM); d. Mix the drug-resin granules with the diluent, colorant, and disintegrant in a double-cone blender for about 10 - 20 minutes; e. Mix the product from step (d) with the sieved sweetener, flavor, and lubricant in a double-cone blender for about 4 - 8 minutes; and f. Compress the mixed components directly into ODT.

[0094] For the compression of the orally disintegrating tablets, a die punch tool with a 10.5 mm round-shaped punch was used. In some embodiments, any other suitable size or shape of tool can be used. In some embodiments, the ODT can be manufactured using a dry granulation process. The prepared tablets showed a hardness of about 3 - 12 kp and a disintegration time of less than 1 minute, preferably 10 - 30 seconds.

[0095] The following exemplary ODT formulations containing drotaverine were prepared by the preparation method exemplified above herein while varying the amount of the drug - resin complex.

[0096] Example 3: An exemplary formulation containing drotaverine was prepared using a drug - resin complex.

[0097] [Table 1]

[0098] Example 4: An exemplary formulation containing drotaverine was prepared using a drug - resin complex.

[0099] [Table 2]

[0100] Example 5: An exemplary formulation containing drotaverine was prepared using a drug - resin complex.

[0101] [Table 3]

[0102] Example 6: An exemplary formulation containing drotaverine was prepared using a drug - resin complex.

[0103] [Table 4]

[0104] Example 7: Using a drug-resin complex, an exemplary formulation containing drotaverine was prepared.

[0105] [Table 5]

[0106] Example 8: Using a drug-resin complex, an exemplary formulation containing drotaverine was prepared.

[0107] [Table 6]

[0108] Example 9: Using a drug-resin complex, an exemplary formulation containing drotaverine was prepared.

[0109] [Table 7]

[0110] Example 10: Using a drug-resin complex, an exemplary formulation containing drotaverine was prepared.

[0111] [Table 8]

[0112] Example 11: Using a drug-resin complex, an exemplary formulation containing drotaverine was prepared.

[0113] [Table 9]

[0114] Example 12: Using a drug-resin complex, an exemplary formulation containing drotaverine was prepared.

[0115] [Table 10]

[0116] Example 13: An exemplary formulation containing drotaverine was prepared using a drug-resin complex

[0117] [Table 11]

[0118] Example 14: An exemplary formulation containing drotaverine was prepared using a drug-resin complex

[0119] [Table 12]

[0120] Example 15: An exemplary formulation containing drotaverine was prepared using a drug-resin complex

[0121] [Table 13]

[0122] Example 16: An exemplary formulation containing drotaverine was prepared using a drug-resin complex

[0123] [Table 14]

[0124] Example 17: An exemplary formulation containing drotaverine was prepared using a drug-resin complex

[0125] [Table 15]

[0126] Example 18: An exemplary formulation containing drotaverine was prepared using a drug-resin complex

[0127]

Table 16

[0128] Example 19: Drug Dissolution Test The ODTs prepared using the components exemplified in Tables 1 to 16 above were evaluated using in vitro drug dissolution tests as described in Table 17 below for representative formulations.

[0129] The ODT formulations showed rapid drug release in the oral cavity compared to film-coated tablets of 40 mg and 80 mg. The developed tablets of the present disclosure showed faster drug release. Considering the drug elution tests described herein, the ODT formulations of the present disclosure should lead to more rapid analgesia than currently available film-coated tablets. The ODT formulations achieve approximately 90% drug release in about 5 minutes, as shown in Table 17 below, and thus rapid onset of action is expected.

[0130]

Table 17

[0131] Example 20: Examination of Tablet Hardness and Disintegratability of the ODT of the Present Disclosure Using the steps described in Examples 1 and 2 and the components described in Tables 1 to 16 above, the ODTs prepared showed a hardness of about 3 to 12 kp with a disintegration time of less than 1 minute when placed in 1 to 3 mL of water. For tablets with a hardness of 3 to 5 kp, the disintegration time was about 8 to 12 seconds. For tablets with a hardness of 10 to 12 kp, the disintegration time was about 25 to 30 seconds.

[0132] Example 21: Stability Data The ODT formulations developed according to the present disclosure showed chemical and physical stability using the ICH accelerated stability guidelines (40 °C ± 2 °C and 75% RH ± 5% RH). The accelerated stability data of drotaverine tablets formulated without using a drug-resin complex are shown in Table 18 below, and the accelerated stability data of the ODT using a drug-resin complex according to Example 16 are shown in Table 19 below.

[0133]

Table 18

[0134]

Table 19

[0135] The surprising new formulations and methods for their preparation described in the present disclosure accurately describe the effectiveness and usefulness of these formulations and methods for restoring human healthy functions and treating the human conditions and disorders identified and described in this patent application.

[0136] The subject matter is described herein with reference to its particular preferred embodiments, but other embodiments are possible. By way of example, the formulations of the present disclosure include drotaverine or a salt thereof as an antispasmodic agent. However, those skilled in the art will understand that the scope of the present disclosure extends to formulations containing other antispasmodic agents known in the art.

Claims

1. An oral dosage form comprising drotaverine or a salt thereof and an ion exchange resin, wherein the drotaverine and the ion exchange resin form a drotaverine-ion exchange complex, and the dosage form is formulated as an orally disintegrating tablet.

2. An oral dosage form comprising drotaverine or a salt thereof and a flavor enhancer, wherein the dosage form is formulated as an orally disintegrating tablet.

3. The oral dosage form according to claim 2, wherein the dosage form further comprises a bitter masking flavor.

4. The oral dosage form according to any one of claims 1 to 3, wherein the dosage form contains 2.5 to 100 mg of drotaverine or a salt thereof.

5. The oral dosage form according to any one of claims 1 to 4, wherein the dosage form contains drotaverine hydrochloride.

6. The oral dosage form according to any one of claims 2 to 5, further comprising an ion exchange resin, wherein the drotaverine and the ion exchange resin form a drotaverine-ion exchange complex, and the dosage form is formulated as an orally disintegrating tablet.

7. The oral dosage form according to claim 1 or 6, wherein the ion exchange resin is Kyron 114, Kyron 314, Indion 204, Indion 234, Indion 294, or a combination thereof.

8. The oral dosage form according to any one of claims 1, 6 or 7, wherein the ratio of drotaverine to the ion exchange resin is 1:2 to 1:

6.

9. The oral dosage form according to any one of claims 1 or 6 to 8, wherein the oral dosage form is in the form of granules, and the size of the granules ranges from about 850 microns to 300 microns.

10. The oral dosage form according to any one of claims 1 to 9, wherein the dosage form has a hardness of 3 to 12 kp.

11. The oral dosage form according to any one of claims 1 to 10, wherein the dosage form disintegrates in the oral cavity within 60 seconds or less without water.

12. The oral dosage form according to claim 11, wherein the dosage form disintegrates in the oral cavity within 30 seconds or less without water.

13. The oral dosage form according to any one of claims 1 to 12, wherein the dosage form disintegrates in 1 to 3 mL of water within 60 seconds or less.

14. The oral dosage form according to claim 13, wherein the dosage form disintegrates in 1 to 3 mL of water within 30 seconds or less.

15. The oral dosage form according to any one of claims 1 to 14, further comprising an excipient selected from a diluent, a disintegrant, a flavoring agent, a sweetening agent, a lubricant, a glidant, an anti-adhesive agent, or a combination thereof.

16. The oral dosage form according to any one of claims 1 or 6 to 15, wherein the ratio of the excipient to the drug-resin complex is from 0.05:1 to 2.5:

1.

17. The oral dosage form according to claim 16, wherein the ratio of the excipient to the drug-resin complex is from 0.1:1 to 2:

1.

18. The oral dosage form according to any one of claims 1 to 17, wherein the dosage form further comprises at least one diluent, and the diluent comprises monosaccharides, oligosaccharides, polysaccharides, lactose, sugar alcohols, cellulose powder, microcrystalline cellulose, siliconized microcrystalline cellulose, chemically modified cellulose derivatives, starch, or combinations thereof.

19. The oral dosage form according to any one of claims 1 to 18, wherein the dosage form further comprises at least one disintegrant, and the disintegrant comprises at least one of starch, natural or chemically modified cellulose, microcrystalline cellulose, gums, alginic acid or its salts, sugars, aluminum oxide, or synthetic polymers.

20. The oral dosage form according to claim 19, wherein the level of the disintegrant is in an amount of 1% to 10% w / w.

21. The oral dosage form according to claim 20, wherein the disintegrant is in an amount of 2% to 8% w / w.

22. The oral dosage form according to claim 19, wherein the starch is sodium starch glycolate.

23. The oral dosage form according to claim 19, wherein the natural or chemically modified cellulose is croscarmellose sodium.

24. The oral dosage form according to claim 19, wherein the synthetic polymer is crospovidone.

25. The oral dosage form according to any one of claims 1 to 24, wherein the dosage form further comprises at least one flavoring agent, and the flavoring agent comprises strawberry flavor, cherry flavor, orange flavor, peppermint flavor, blackcurrant flavor, banana flavor, raspberry flavor, red fruit flavor, wild berry flavor, caramel flavor, or combinations thereof.

26. The oral dosage form according to any one of claims 1 to 25, wherein the dosage form further comprises at least one sweetening agent, and the sweetening agent comprises aspartame, acesulfame potassium, sodium saccharinate, neohesperidin dihydrochalcone, sucralose, sucrose, fructose, monoammonium glycyrrhizinate, or combinations thereof.

27. The dosage form further comprises at least one lubricant, and the lubricant comprises sodium benzoate, sodium stearyl fumarate, calcium stearate, magnesium stearate, zinc stearate, glyceryl behenate, stearic acid, glyceryl monostearate, or a combination thereof. The oral dosage form according to any one of claims 1 to 26.

28. An oral dosage form comprising drotaverine or a salt thereof, Kyron 114, microcrystalline cellulose, colloidal silicon dioxide, mannitol, fructose, sucralose, aspartame, crospovidone, sodium stearyl fumarate, fruit flavor, and a bitterness masking flavor, wherein the dosage form is formulated as an orally disintegrating tablet.

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

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

33. The oral dosage form according to any one of claims 1 to 32, wherein the dosage form is stable for 2 years when stored at a temperature of 25 to 30 °C and 60 to 75% RH as long-term storage conditions.

34. The oral dosage form according to any one of claims 1 to 33, wherein the oral dosage form exhibits an improved taste.

35. The oral dosage form according to any one of claims 1 to 34, wherein the oral dosage form exhibits an improved aftertaste.

36. The oral dosage form according to any one of claims 1 to 35, wherein the oral dosage form exhibits an improved palatability.

37. A method for preparing an orally disintegrating tablet of drotaverine or a salt thereof, a. A step of mixing an ion exchange resin with water; b. A step of adding drotaverine or a salt thereof to the ion exchange resin dispersion of the mixture in step a and stirring for a sufficient time to form a drug-resin complex. c. A step of washing the filtered drug-resin complex until the unbound drotaverine drug content is less than 2.0%, and then washing with water until a filtrate is obtained; d. A step of drying the drug-resin complex to form a dried drug-resin complex containing less than 5.0% w / w of moisture; e. A step of pulverizing and sieving the dried drug-resin complex to obtain drug-resin complex granules of appropriate size; f. A step of separately weighing the drug-resin complex granules and at least one excipient; g. A step of passing the drug-resin complex granules and the excipient through a mesh; h. A step of mixing the drug-resin complex granules and the excipient, and subsequently mixing with a disintegrant, a flavoring agent, a sweetening agent, a lubricant, a glidant, and an anti-adhesive agent; i. A step of finally compressing the mixed drug-resin complex granules and the excipient into an orally disintegrating tablet A method comprising.

38. The method according to claim 37, wherein the ion exchange resin comprises Kyron 114, Kyron 314, Indion 204, Indion 234, Indion 294.

39. The method according to claim 37 or 38, wherein the ion exchange resin is mixed with water for 30 to 45 minutes, then drotaverine is slowly added, and mixed for at least 2 to 4 hours.

40. The method according to any one of claims 37 to 39, wherein the ion exchange resin and drotaverine or a salt thereof are mixed in a ratio of 2:1 to 6:

1.

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

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

43. The method according to any one of claims 37 to 42, wherein the dried drug-resin complex is sieved with a mesh, and the size of the mesh is 850 microns or less.

44. The method according to any one of claims 37 to 43, wherein the drug-resin complex granules and the excipient are mixed for 10 to 20 minutes.

45. The method according to any one of claims 37 to 44, wherein the orally disintegrating tablet is formed using a direct compression method, a dry granulation method, a wet granulation method, or a fluidized bed preparation method.

46. The dosage form according to any one of claims 1 to 36, or the method according to any one of claims 37 to 45, wherein at least 90% of the orally disintegrating tablets dissolve in vitro within 5 minutes using a paddle at 40 RPM in a 0.1 N HCl dissolution medium.

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

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

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