TR2023013064A2 - PEDIATRIC GUMMY FORMULATIONS CONTAINING BILASTINE AND PHENYLEPHRINE TOGETHER IN THE TREATMENT OF SEASONAL ALLERGIC RHINITIS AND NASAAL DECONJECTION - Google Patents

Abstract

This invention; It is a Gummy formulation that contains an antihistamine and an oral decongestant active ingredient for the treatment of pediatric patients suffering from seasonal allergic rhinitis and nasal congestion, and can be easily used without the need for water for the comfort of patients with swallowing problems. Pediatric patients suffering from seasonal allergic rhinitis and nasal congestion Two pharmaceutical active substances used separately for the drug have been turned into a single combined drug form, thus accelerating the pharmacological effect, reducing and/or minimizing side effects, and at the same time eliminating the economic disadvantage of supplying two separate drugs separately; As an alternative dosage form for patients who have difficulty swallowing solid dosage forms or who are bedridden or have mental problems, the Gummy dosage form, which contains the combination of the active ingredients Bilastine and Phenylephrine HCl, can be used safely even when there is no access to water and helps pediatric patients suffering from seasonal allergic rhinitis and nasal congestion. It is about innovative Gummy dosage formulations that can increase the standard of

Description

DESCRIPTION PEDIATRIC GUMMY FORMULATIONS CONTAINING BILASTIN AND PHENYLEPHINE TOGETHER FOR THE TREATMENT OF SEASONAL ALLERGIC RHINITIS AND NASAL DECONGESTION Technical Field This invention; It relates to the innovative Gummy dosage formulations in the form of chewable gel tablets developed to provide two effective drugs (Bilastine and Phenylephrine HCI) together in a single combined drug form (Gummy) to relieve nasal congestion and/or alleviate the symptoms of diseases such as allergic rhinitis and ulcers due to nutrition, environment, climate and various reasons, to accelerate the pharmacological effect, to reduce and/or minimize side effects, to eliminate the economic disadvantage of taking two separate drugs, to facilitate drug use for children, to develop an alternative dosage form for child patients who have difficulty swallowing solid dosage forms or who are bedridden or have mental problems, to be able to use the medicine safely even when there is no access to water and, most importantly, to increase the standard of life of child patients with allergies. The product of this invention combines two active pharmaceutical ingredients (Bilastine and Phenylephrine HCl), currently available in separate dosage forms on the pharmaceutical market, for the treatment of allergic rhinitis and nasal congestion, into an innovative dosage form (Gummy) that offers advantages in terms of both cost-effectiveness and patient compliance for pediatric use. State of the Art: Allergic rhinitis is defined as an allergic disease characterized by symptoms of sneezing, nasal itching, airflow obstruction, and mostly clear nasal discharge caused by IgE-mediated reactions to inhaled allergens, including mucosal inflammation. Allergic rhinitis is an allergic disorder that can negatively impact quality of life, even impairing work or school productivity. Allergic conjunctivitis is a common comorbidity in patients with allergic rhinitis and is characterized by symptoms of non-nasal tearing, ocular burning, redness, and itching. Allergic rhinitis is a common condition that can significantly impact a patient's quality of life. Diagnosis is established by a comprehensive history and physical examination. Further diagnostic testing, usually using adult allergy testing or allergen-specific IgE testing, is required to confirm that underlying allergies are also causing the rhinitis. Current therapeutic options for the treatment of allergic rhinitis are effective in managing symptoms and are generally safe and well tolerated. Important allergens that cause allergic rhinitis include seasonal pollens and molds, as well as perennial indoor allergens such as dust mites, pets, and insects. The prevalence of sensitization to respiratory allergens is increasing and currently exceeds 40% in many populations in the United States (US) and Europe. Allergic rhinitis is ranked sixth among the most common chronic diseases in the US, surpassing heart disease. The disease can begin at any age, but the highest incidence occurs in childhood and adolescence. Allergic rhinitis affects one in five people worldwide. In addition to the known symptoms of allergic rhinitis, it also has side effects that significantly affect quality of life by reducing itching, red, watery eyes, itchy throat and palate, sleep disturbance, productivity, learning, and focus. The sedation caused by antihistamines, which are frequently used in the treatment of allergic rhinitis, reduces productivity; It negatively impacts children and adolescents' academic performance. Allergic rhinitis also causes sleep problems. For example, allergic rhinitis has been reported to result in 3.5 million lost workdays and 2 million lost school days each year in the United States. Urticaria is also defined as a skin allergy. Characteristic symptoms include itchy skin lesions with central swelling, painful areas involving the skin and mucous membranes (angioedema). It is characterized by the sudden development of transient hives (wheals), angioedema, or both. It has been reported to be histamine-mediated. Oral antihistamines are an essential part of the initial treatment of acute allergic reactions. Oral antihistamines are one of the mainstays of treatment for allergic rhinitis (seasonal or perennial). They relieve or eliminate symptoms such as sneezing, runny nose, and itching. Histamine plays a significant role in the skin lesions characteristic of urticaria. Antihistamines are a group of drugs that inhibit histamine receptors. Antihistamines reduce the number and size of urticarial lesions and help relieve itching. They are generally structurally similar to histamine and act by blocking histamine-receptor interaction. Bilastine is a second-generation H1 histamine antagonist recently approved for the symptomatic treatment of allergic rhinitis and chronic urticaria. Bilastine is a potent and highly selective antihistamine used orally for the symptomatic treatment of seasonal or perennial allergic rhinitis, rhinoconjunctivitis, and urticaria. It is indicated for the symptomatic treatment of allergic disorders in adults and children. Bilastine's efficacy and good tolerability profile, lack of sedation-inducing potential, allow for long-term administration without impairment of performance or learning abilities. Bilastine, which cannot cross the blood-brain barrier and therefore has fewer sedative side effects, has become the preferred choice among experts, particularly with its long duration of action and performance-neutral treatment protocol. Furthermore, its cardiac safety has been confirmed at therapeutic and supratherapeutic doses. Clinical trials of bilastine have shown its effectiveness in relieving nasal and ocular symptoms of allergic rhinitis and wheals and itching in urticaria. Phenylephrine is a sympathomimetic drug used as a nasal decongestant. It is indicated for the temporary relief of nasal congestion caused by the common cold or allergic rhinitis. Phenylephrine is widely used in pharmaceutical formulations for its decongestant properties. A vasoconstrictor, phenylephrine has both direct and indirect sympathomimetic effects. It causes vasoconstriction, which limits the amount of fluid entering the nose, throat, and sinus cavities and reduces inflammation of the nasal membranes. Phenylephrine is generally recognized as safe and effective by the U.S. Food and Drug Administration (FDA). The use of oral phenylephrine instead of pseudoephedrine is encouraged in many allergy, cold, and cough medications. The combination of an antihistamine and a nasal decongestant is widely preferred for the treatment of upper respiratory tract disorders and allergic symptoms in the pediatric population. Antihistamine/nasal decongestant combinations are widely used to maximize seasonal allergic rhinitis treatment. Currently, the medication groups used in the treatment of allergic diseases are mostly in conventional tablet form. These treatments can cause undesirable side effects, and the need for water for administration also poses compliance issues, particularly for patients with dysphagia (difficulty swallowing). Furthermore, these conditions are more common in pediatric patients. To overcome these challenges, the pharmaceutical industry and current pharmaceutical technologies are working on new generation drug dosage forms to improve patient living standards. Gummy (gel) dosage forms are attracting attention because they do not require water for consumption and are easy to chew. This dosage form has been found to be more suitable for children and elderly patients with swallowing difficulties. They are generally created by adding gelatin as a gelling agent to syrup, where carbohydrates such as sugar and starch syrup are boiled, then cooled and solidified. These formulations, to which the active ingredient is also added, are crushed and swallowed. Therefore, it is thought that this formulation will contribute to improving medication adherence in the daily lives of patients with poor medication adherence. The availability of chewable, non-bitter, and water-free dosage forms is important for improving compliance in infants and children. Gummies, which are easy to use without water and swallowing, are critical for ensuring patient compliance and achieving the expected therapeutic effects in drug-based treatments. Pediatric drug development necessitates the availability of safe and easy-to-use dosage formulations for clinical application. Chewable tablets are a widely used pediatric dosage form. In pediatrics, the concepts of "pediatric-specific" or "personalized" dosage forms are emerging as an alternative to traditional pharmaceutical split-dose formulations. In recent years, new technologies emerging in personalized treatments have disrupted the development and production of traditional pediatric preparations. These technologies enable multidrug combinations, allowing for the production of patient-specific preparations and the implementation of pediatric-friendly dosage forms. Consequently, with the old technique/method, Bilastine is available on the global pharmaceutical market only as a solid dosage form in tablets, while phenylephrine is available as drops, syrup, or tablets as a solid dosage form. Therefore, patients wishing to use these two active ingredients must use these medications separately. In other words, these two active pharmaceutical ingredients are not available in a combined dosage form in the world pharmaceutical market. Especially pediatric and geriatric patients have difficulty swallowing solid dosage forms. Many pediatric and geriatric patients are reluctant to take solid dosage forms (tablets, capsules) due to fear of choking. Rapid relief of seasonal allergic rhinitis and other allergic symptoms is possible only with dosage forms that are offered in solid dosage forms and are available in the pharmaceutical market only as tablets without any alternatives. Bilastine and Phenylephrine cannot provide rapid pharmacological effects with their current dosage forms. Individualized doses of Bilastine and Phenylephrine cannot be administered to pediatric and geriatric patients with their current dosage forms (tablets, capsules, etc.). The economic disadvantage of purchasing two separate drugs separately is that it is economically disadvantageous for both individuals and reimbursement institutions. Pediatric patients with allergic bodies who have difficulty swallowing solid dosage forms or who are bedridden or have mental problems can take these two active substances in a single dosage form. There are deficiencies and disadvantages such as not being able to use them together in their form, not being able to use tablets or capsules when there is no access to water, and the lack of alternative, innovative dosage forms that increase patient compliance in combination medications for these disease groups for the pediatric patient group. When the studies in the current state of the art are examined, it is seen that there is a need for formulations developed for oral use that aim to solve multiple problems simultaneously and make a product that is both economical and advantageous in terms of patient compliance. Description of the Invention In this description, the invention is explained only for a better understanding of the subject and in a way that does not create any limiting effects. The structural and characteristic features of the invention and all its advantages will be more clearly understood thanks to the detailed description written below, and therefore the evaluation should be made considering this description. The present invention relates to gummy dosage form formulations that meet the aforementioned requirements, eliminate all disadvantages, and offer some additional advantages. Using an innovative formulation design, gummies containing Bilastine and Phenylephrine HCl rapidly disintegrate upon contact with saliva within the oral cavity. This design enhances the absorption of these active ingredients from the oral mucosa, thereby accelerating their pharmacological effects. The aim is to improve the standard of living and comfort of all pediatric patients suffering from seasonal allergic rhinitis and nasal congestion. A review of dosage forms currently in use in the global pharmaceutical market reveals that no pharmaceutical dosage form containing both Bilastine and Phenylephrine HCl simultaneously and offering a rapid onset of action exists in the pharmaceutical market or in literature studies. Many pharmaceutical preparations are administered in tablet, granule, powder, and liquid forms. Tablets are generally designed to be swallowed or chewed to deliver a precise dose of medication to patients. However, some patient groups, particularly pediatric and geriatric patients, have difficulty swallowing or chewing solid dosage forms. Many pediatric and geriatric patients are reluctant to take these solid dosage forms due to fear of choking. Tablets provide the highest dose homogeneity and offer the best content uniformity among all oral dosage forms. Furthermore, tablets offer the most cost-effective manufacturing options. However, this method, which is difficult to implement for pediatric and elderly populations, has highlighted the need for a new, orally administered medication form. Recent advances in technology have led to the development of alternative dosage forms, such as new-generation "gummies," for patients who have difficulty swallowing solid dosage forms such as tablets and capsules (dysphagia). Today, innovative formulation designs and the transition from existing conventional dosage forms to innovative dosage forms are increasingly common in many prescription and nonprescription product groups, particularly for coughs, colds, sore throats, erectile dysfunction, allergic reactions, asthma, gastrointestinal disorders, hypertension, pain treatments, snoring complaints, sleep problems, and multivitamin combinations. The pharmaceutical industry continues to transform conventional medications into gummies. This new-generation dosage form aims to eliminate the psychological factors associated with using tablets/capsules for patients of all ages who experience dysphagia, also known as difficulty swallowing. Furthermore, its water-free use allows for easy medication administration even during travel or when water is unavailable. The main advantage of this dosage form is that The rapid onset of the drug's pharmacological effects. This dosage form, which undergoes rapid disintegration and subsequent dissolution in the mouth, particularly through the capillaries passing through the cheek and sublingual area, also ensures rapid absorption of the active ingredients into the bloodstream and rapid onset of pharmacological action. In addition to providing effective treatment using lower doses of Bilastine and Phenylephrine HCl, it may also be possible to reduce and/or minimize side effects associated with the active ingredients. This drug formulation, which is completely disintegrated and dispersed in the mouth before entering the gastrointestinal tract, overcomes the first-pass effect with rapid absorption from the oral mucosal membranes and continues with absorption in the gastrointestinal system via swallowed drug formulation particles. In addition to providing effective treatment using lower doses of Olmesartan and HCTZ nanocrystals, It may also be possible to reduce and/or minimize the side effects caused by the active ingredients. This drug formulation, which is completely dissolved and dispersed in the mouth before passing into the gastrointestinal tract, will also prevent the first-pass effect and delays in absorption in the gastrointestinal tract. Gummies are one of the innovative solid drug forms that can be disintegrated/dissolved/dispersed in less than a minute when placed in the mouth and can be used without the need for water. Gummies are soft, flexible, and chewing gum-like drug formulations prepared using hydrophilic polymers. Thanks to their gel structure, they can be quickly broken down by teeth and provide rapid dissolution/dispersion on contact with saliva. Gummies, which contain two active ingredients we developed, have many unique advantages. These include: i. Avoiding the first-pass effect of the active ingredients and providing rapid action even at low doses, ii. No water requirement, iii. No risk of drowning, iv. Less risk of side effects due to containing low dose of active ingredient, v. Providing rapid effect in emergency situations, vi. Easy masking of taste and leaving a pleasant taste in the mouth, vii. Providing ease of application, viii. Leaving little or no residue in the mouth after use, ix. Preserving stability, x. Not affecting the functioning of mouth functions, xi. Being applicable for hydrophobic drugs that are insoluble in water and increasing their bioavailability. The primary purpose of the invention; In addition to offering a faster onset of action compared to conventional dosage forms due to its gummy form, it also allows all pediatric patients suffering from seasonal allergic rhinitis and nasal congestion, including dysphagic, bedridden, or mentally disabled patients, to comfortably take their medications whenever and wherever they need them, without the need to swallow. Another purpose of the invention is to introduce an innovative drug dosage formulation (Gummy) to the pharmaceutical market that can be easily used by all pediatric patients suffering from seasonal allergic rhinitis and nasal congestion, even in situations where access to water is not possible. To achieve the aforementioned objectives, this invention includes formulations in Gummy dosage forms containing the combination of Bilastine and Phenylephrine HCl. Using an innovative formulation design, gummies containing Bilastine and Phenylephrine HCl will rapidly disintegrate upon contact with saliva in the oral cavity, increasing the absorption of these active ingredients from the oral mucosa and thus accelerating their pharmacological effects. This will improve the quality of life and comfort of all pediatric patients suffering from seasonal allergic rhinitis and nasal congestion. Using lower doses of Bilastine and Phenylephrine will not only provide effective treatment but also reduce and/or minimize side effects associated with the active ingredients. This formulation, which is completely dissolved and dispersed in the mouth before reaching the gastrointestinal tract, will also prevent first-pass effects and delays in relieving symptoms due to absorption in the gastrointestinal tract. Additionally, the gummy formulations in our study offer advantages over older techniques, including the ability to rapidly alleviate and/or eliminate symptoms in patients with allergies or those experiencing an allergic emergency (especially compared to conventional tablets, which are available only as tablets in the pharmaceutical market without alternatives, in solid dosage forms); to prevent lost workdays in the allergic pediatric population by combining Bilastine and Phenylephrine; and to reduce the budget for two medications to a single medication from an economic perspective. A gummy dosage form formulation, in its most basic form, contains a combination of Bilastine and Phenylephrine HCl. In the invention, the ratio of Bilastine to Phenylephrine HCl is preferably 2:1. In all preferred embodiments of the invention, the developed film contains 0.5 mg of Bilastine and 5 mg of Phenylephrine HCl. The invention, which is in the form of a gummy, is placed on the base of the tongue, wetted with saliva within 5-10 seconds and subsequently disintegrated by chewing. In this way, the active ingredients in the Gummy are released and dispersed and/or dissolved for local and/or systemic absorption. With the developed invention, drug dosage forms containing both active ingredients at the same time and offering a rapid onset of action have been prepared. All excipients used in the developed formulation are water-soluble or swell in water. In other words, these prepared Gummies are disintegrated, dispersed and dissolved very quickly with saliva when placed on the tongue base. Therefore, a rapid It is possible to obtain pharmacological effects, use it without the need for water and difficulty swallowing. This allows for a rapid onset of action and provides rapid resolution of the patient's complaints. Because the oral mucosa has a thin membrane structure and a high number of blood vessels, it has high permeability. This rapid blood flow results in very rapid bioavailability. With the rapid absorption of active substances released as a result of this breakdown in the mouth, absorption from the gastrointestinal tract is bypassed, eliminating the first-pass effect through the liver. This rapid bioavailability stems from bypassing the first-pass effect and better permeability. Furthermore, the large surface area for absorption and ease of application make the oral mucosa a very effective and selective route for systemic drug transport. In this way, it is effective in all seasonal allergic reactions. It is ensured that pediatric patients suffering from rhinitis and nasal congestion can easily take these drugs in combination on the tongue, without using tablets or capsules, by chewing, breaking and swallowing with saliva without requiring water. In a preferred embodiment of the invention, the developed formulation preferably contains at least one excipient from the following groups in accordance with the amounts given in Table 1, Table 2 and Table 3: Pectin, Gelatin, Sodium alginate, Agar agar, Chitosan, Polymerized resin, Hydroxy propyl methyl cellulose (HPMC) E15, Hydroxy propyl methyl cellulose (HPMC) E50, Hydroxy propyl methyl cellulose (HPMC) K100, Hydroxy ethyl cellulose (HEC), Carboxy methyl cellulose (CMC), Sodium carboxy methyl cellulose (NaCMC), Methyl cellulose (MC), Maltodextrin, At least one natural polymer selected from the group comprising Pullulan, Polyvinylpyrrolidone (PVP), Polyvinyl alcohol (PVA), Polyethylene glycol (PEG) 300, Polyethylene glycol (PEG) 800, Polyethylene glycol Gum Arabic, Xanthan gum, Carnauba wax or a combination thereof (more preferably a combination of Gelatin, Gum Arabic, HPMC E15 and Carnauba wax; Table 1); Pectin, Gelatin, Sodium alginate, Agar agar, Chitosan, Polymerized resin, Hydroxy propyl methyl cellulose (HPMC) E15, Hydroxy propyl methyl cellulose (HPMC) E50, Hydroxy propyl methyl cellulose (HPMC) K100, Hydroxy ethyl cellulose (HEC), Carboxy methyl cellulose (CMC), Sodium carboxy methyl cellulose (NaCMC), Methyl cellulose (MC), Maltodextrin, Pullulan, Polyvinylpyrrolidone (PVP), Polyvinyl alcohol (PVA), Polyethylene glycol (PEG) 300, Polyethylene glycol (PEG) 800, Polyethylene glycol Gum Arabic, Xanthan gum, Carnauba wax or a combination thereof (more preferably Gelatin, Xanthan gum, Agar agar, PEG 4000 and Carnauba wax combination; Table 2); Pectin, Gelatin, Sodium alginate, Agar agar, Chitosan, Polymerized resin, Hydroxy propyl methyl cellulose (HPMC) E15, Hydroxy propyl methyl cellulose (HPMC) E50, Hydroxy propyl methyl cellulose (HPMC) K100, Hydroxy ethyl cellulose (HEC), Carboxy methyl cellulose (CMC), Sodium carboxy methyl cellulose (NaCMC), Methyl cellulose (MC), Maltodextrin, Pullulan, Polyvinylpyrrolidone (PVP), Polyvinyl alcohol (PVA), Polyethylene glycol (PEG) 300, Polyethylene glycol (PEG) 800, Polyethylene glycol, Gum arabic, Xanthan gum, Carnauba wax or a combination thereof (more preferably at least one natural polymer selected from the group consisting of Gelatin, Xanthan gum, Maltodextrin, PEG 4000 and Carnauba wax combination; Table 3); At least one elasticizer (more preferably Glycerol) selected from the group comprising Glycerol, Propylene glycol, Sorbitol solution (50%, 60% or 70%), PEG 800, PEG 400, PEG 300 or a combination thereof, which provides flexibility of the Gummies; At least one saliva secretion agent (more preferably Citric acid) selected from a group comprising Citric acid, Ascorbic acid, Lactic acid or Tartaric acid; At least one sweetener selected from a group comprising Aspartame, Sodium saccharin, Stevia, Sucralose, D-Mannitol, Mannitol 1600 or Acesulfame (more preferably Sodium saccharin; Table 1, Table 2 and Table 3); At least one sweetener selected from a group comprising Aspartame, Sodium saccharin, Stevia, Sucralose, D-Mannitol, Mannitol 1600 or Acesulfame; at least one sweetening agent selected from a group comprising Aspartame, Sodium saccharin, Stevia, Sucralose, D-Mannitol, Mannitol 1600 or Acesulfame (more preferably Mannitol 160C; Table 3); at least one superdisintegrant (more preferably Sodium starch glycolate) selected from the group comprising Corscarmellose sodium, Kollidon CL, Xanthan gum, Crospovidone, Sodium starch glycolate, Hydroxypropyl cellulose, Ac-Di-Sol®, Solutab®, Nymce ZSX®, Primellose®, Vivasol®, Polyplasdone®, Explotab®, Primojel®, Satialgine®, Sodium bicarbonate or a combination thereof and ensuring rapid disintegration of the Gummies; Instead of vanillin, At least one flavoring agent (more preferably Vanillin) selected from a group comprising Caramel, Neroli, Eucalyptol, Mint, Orange, Cinnamon or Chocolate flavoring; xi. Contains distilled water. Ingredient Name Available amount by weight (%) Bilastine 0.25-5.00 Phenylephrine HCl 0.25-5.00 Gelatin 15.00-40.00 Gum arabic 5.00-20.00 Carnauba wax 0.50-7.50 Glycerol 2.50-10.00 Sodium saccharin 0.25-5.00 Sodium starch glycolate 0.50-10.00 Citric acid 0.50-10.00 Distilled water 20.00-45.00 Ingredient Name Available amount by weight (%) Bilastine 0.01-5.00 Phenylephrine HCI 0.01-5.00 Gelatin 10.00-40.00 Xanthan gum 5.00-25.00 Glycerol 0.50-10.00 Citric acid 0.50-10.00 Sodium starch glycolate 0.50-10.00 Sodium saccharin 0.50-5.00 Carnauba wax 0.50-10.00 Distilled water 20.00-50.00 Ingredient Name Available amount by weight (%) Bilastine 0.01-5.00 Phenylephrine HCI 0.01-5.00 Gelatin 15.00-35.00 Xanthan gum 5.00-20.00 Maltodextrin 2.50-15.00 Glycerol 0.50-10.00 Carnauba wax 0.50-10.00 Citric acid 0.10-7.50 Sodium starch glycolate 0.50-10.00 Sodium saccharin 0.50-10.00 Distilled water 25.00-60.00 In a preferred embodiment of the invention, the formulation developed contains Bilastine, Phenylephrine HCI, Gelatin, Gum arabic, HPMC E15, Carnauba wax, Glycerol, Sodium saccharin, Sodium starch glycolate, Mannitol 160C, Vanillin, Citric acid and Distilled water. In a preferred embodiment of the invention, the formulation developed contains Bilastine, Phenylephrine HCI, Gelatin, Xanthan gum, Agar Agar, PEG 4000, Glycerol, Mannitol 160C, Citric acid, Sodium starch glycolate, Vanillin, Sodium saccharin, Carnauba wax and distilled water. The formulation developed in a preferred embodiment of the invention contains Bilastine, Phenylephrine HCI, Gelatin, Xanthan gum, Maltodextrin, PEG 4000, Glycerol, Carnauba wax, Vanillin, Citric acid, Sodium starch glycolate, Vanillin, Sodium saccharin and distilled water. In an exemplary embodiment of the invention, the developed formulation is prepared by following the following process steps: The required amount of distilled water is added into a beaker on a precision balance with a precision of at least 1 mg. All components that make up the formulation for gummies are weighed on a precision balance with a precision of at least 1 mg; Mixing the weighed components preferably at 500 rpm by heating them first at 40-50 ° C for at least 10 minutes, then stirring for at least 2 hours and dissolving or dispersing all components (except Bilastine and Phenylephrine HCl); then adding Bilastine and Phenylephrine HCl to this mixture; pouring the mixture into a mold; drying the mixture poured into the mold for preferably 6-72 hours (preferably 48 hours) at room temperature (preferably 25 ° C) and removing the Gummies from the mold so that they contain the specified amount of Bilastine and Phenylephrine HCl in each mold; storing them in separate zip-lock bags, away from moisture, heat and light, at room temperature (25 ° C) until use.TR TR TR TR TR TR TR TR TR TR TR TR TR TR TR TR TR TR TR

Claims (1)

1.