TR2023019879A2 - ORAL THIN FILM FORMULATIONS CONTAINING COLCHISINE AND FEBUXOSTAT NANOCRYSTALS TOGETHER - Google Patents

Abstract

This invention is a thin drug that is developed to provide rapid and effective treatment of pain and inflammation in gout as well as to increase life comfort, synergistically containing the effects of Colchicine and Febuxoxate for effective use in the treatment of gout, and quickly dispersing/dissolving in the mouth. It relates to films/strips formulations.

Description

DESCRIPTION COMBINING COLLICIN AND FEBUCSOSTAT NANOCRYSTALS Technical Field This invention relates to fast-dissolving/dissolving thin films/strips formulations containing Colchicine and Febuxoxate synergistically to be used effectively in the treatment of gout and developed for the rapid and effective treatment of pain and inflammation in gout as well as to increase the comfort of life. State of the Art Gout is an autoinflammatory disease characterized by the accumulation of monosodium urate crystals in synovial joints and other tissues in the presence of hyperuricemia. Acute gouty arthritis flares are characterized by the rapid onset of severe pain, swelling, warmth, erythema and decreased motion in the affected joint. Chronic gout is characterized by bone erosions and cartilage damage resulting from long-term joint inflammation. Currently, there are two strategies for gout treatment: First, oral treatments such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, colchicine, or interleukin-1 inhibitors. The second and most important strategy is treatments aimed at potentially lowering urate levels. Colchicine is an anti-inflammatory and analgesic drug and is indicated for the relief of acute gout flares. It is also known to suppress inflammation. Urate-lowering treatments include the use of xanthine oxidase inhibitors. Febuxostat, a xanthine oxidase inhibitor, is approved for the treatment of hyperuricemia in adults with gout, a condition characterized by urate accumulation. Patients taking urate-lowering medications are recommended to be treated concurrently with NSAIDs, colchicine, or low-dose corticosteroids to prevent flares. The combined use of febuxostat and colchicine in oral gout treatments has gained importance in terms of treatment effectiveness. Combination therapies offer better efficacy, less toxicity, more effective treatment, and less potential for drug resistance. However, these treatments are often administered in solid dosage forms, and geriatric and pediatric patients, in particular, have difficulty chewing or swallowing these medications. Furthermore, dysphagic patients (who have difficulty swallowing) who fear choking are reluctant to take these solid dosage forms. To meet this need, the pharmaceutical industry has accelerated its research into innovative dosage forms. One such dosage form is the oral-dissolving thin film (OTF). OTFs are gaining popularity today as dosage forms that increase patient compliance because they can be used without water and dissolve and disperse without leaving a residue when placed on the tongue. Size reduction techniques, one of the strategies for increasing the solubility of water-insoluble drugs, contribute significantly to increasing the bioavailability of drugs. One of these strategies is nanocrystals using nanotechnology. Bioavailability is also increased thanks to the increased surface area provided by reducing the size of water-insoluble drugs, in particular. Gout is a disease that can manifest with various clinical manifestations related to lifestyle and diet. It is also an inflammatory arthropathy characterized by the deposition of monosodium urate crystals in synovial joints and other tissues in the presence of hyperuricemia. Uric acid formation in joints due to hyperuricemia It is characterized by pain, redness, and swelling in the joints caused by the accumulation of uric acid crystals. Uric acid crystals precipitate more rapidly at low temperatures, so the toes, fingers, hands, feet, elbows, and ears are areas where gout flares are seen and where uric acid crystals accumulate in soft tissues (gouty tophi). Uric acid crystals can also accumulate in the urinary tract. Approximately two-thirds of uric acid is excreted in the kidneys and one-third in the intestines. At normal physiological pH, uric acid circulates in the form of ionized urate. Gout is divided into four stages: asymptomatic deposits in the tissues, acute gout, critical periods, and chronic gout. Acute gout is an inflammatory arthritis common in the adult population. Acute gouty arthritis flares are characterized by rapid onset of severe pain, swelling, warmth, It is characterized by erythema and decreased movement. Although pain is the primary symptom, effective treatment for acute gouty arthritis must target both the pain and the underlying inflammation. Acute gout treatment can be managed with rest, ice, and oral NSAIDs, low-dose colchicine, or corticosteroids. The asymptomatic period between gout attacks is critical. This period can last months or even years. However, in untreated patients, attacks tend to be more frequent, prolonged, and severe. Chronic gout is characterized by long-term joint inflammation that causes joint pain at rest or with movement. Chronic gout manifests as chronic synovitis, bone erosions, and cartilage damage. If hyperuricemia persists, monosodium urate crystal deposits also induce chronic inflammatory responses, referred to as chronic gouty arthritis or chronic gout, which can lead to damage to joint structures. Given the high incidence of gout and the challenges of current treatment methods, it is necessary to find new, effective, and safe gout medications or treatments to reduce the heavy economic burden and severe physical and psychological pain caused by long-term medication use. Gout treatment encompasses two strategies. The first is treatment of inflammatory arthritis with NSAIDs, corticosteroids, colchicine, or interleukin-1 inhibitors. The second and most important strategy is to lower the urate level to 0.36 mmol/L (6 mg/dL). This includes uric acid-lowering medications, medications that inhibit uric acid production, medications that increase uric acid excretion, and medications that sequester uric acid, a key factor in gout development. Acute gout treatment includes the prompt use of NSAIDs, colchicine, or corticosteroids. These are effective when initiated early, for example, after It is most effective within the first 24 hours after onset. In the treatment of chronic gout, uricosuric medications work to lower blood uric acid levels by increasing the amount of uric acid excreted by the kidneys. Lowering uric acid levels is key to avoiding gout flares. Allopurinol and febuxostat are first-line medications for preventing recurrent gout. Colchicine and/or probenecid are preferred for patients who cannot tolerate first-line medications or for whom first-line agents are ineffective. Patients taking urate-lowering medications should be treated concurrently with NSAIDs, colchicine, or low-dose corticosteroids to prevent flares. Traditional anti-inflammatory and analgesic medications include colchicine, NSAIDs, and glucocorticoids. Colchicine is an alkaloid extracted from plants of the genus Colchicum sp. Therapeutic uses of colchicine in gout and familial Mediterranean fever. Because of its high cytotoxicity, it has a narrow therapeutic index and frequent toxic reactions. Colchicine is effective at a dose of 0.5 mg two to three times daily. For gout prophylaxis, the dose of colchicine is once or twice daily in adults and individuals 16 years and older. Urate-lowering therapies include xanthine oxidase inhibitors, uricosuric agents, and recombinant uricase therapies. The goal of urate-lowering therapy is to reduce serum urate until a target subsaturation concentration of uric acid of 6.8 mg/dL or less is achieved. Untreated gout can lead to progressive monosodium urate crystal deposition, the development of joint erosions, and chronic gouty arthritis. Therefore, urate-lowering therapy has benefits. Xanthine oxidase inhibitor drugs include allopurinol, febuxostat, and topiroxostat. Xanthine oxidase inhibitors are primarily used to treat gout. They reduce uric acid production and thus prevent the formation of monosodium urate crystals. Hyperuricemia is characterized by elevated uric acid levels in the blood, which can lead to gout, a common condition. Febuxostat, a selective nonpurine inhibitor of both the oxidized and reduced forms of xanthine oxidase, is FDA-approved for the treatment of hyperuricemia in gout. Febuxostat inhibits the function of xanthine oxidase by forming a stable complex with both the reduced and oxidized forms of the enzyme. The recommended daily dose of febuxostat is 40 mg. Febuxostat has been approved for the treatment of chronic hyperuricemia in conditions characterized by urate accumulation. It is being used in gout patients who cannot take allopurinol due to intolerances and adverse reactions. It can also be used in cases of drug-drug interactions. Additionally, patients with chronic gout or very high serum uric acid levels (greater than 10 mg/dL) may benefit from the higher potency of febuxostat compared to allopurinol at fixed doses. Although tablets are the most commonly used oral dosage form, they have several disadvantages that hinder patient compliance. These include poor bioavailability, poor solubility, and limited efficacy. The use of newer-generation dosage forms can largely eliminate these disadvantages, increase the applicability of pharmaceutical compounds, and improve their efficacy. This allows for the correction of low water solubility, tolerance of pH changes, and control of the drug's release mechanism. Consequently, the amount of active ingredient used is reduced, facilitating administration and reducing and/or eliminating observed side effects. This can improve patient compliance and comfort of life. Among these systems, considerable work has been conducted on the preparation of nanoparticles using nanotechnology. Among these systems, nanosuspensions have become the most suitable dosage forms for administration of poorly water-soluble active ingredients. Their high drug content (almost 100%) offers numerous advantages. These include achieving adequate therapeutic concentrations, ensuring efficient transport of drugs into cells, and enhancing pharmacological efficacy. Furthermore, using nanoparticles can reduce the side effects of drugs that cause toxicity when administered in traditional dosage forms. Therefore, due to the low water solubility of febuxostat, nanosuspensions (nanoparticles, nanocrystals) have been prepared with this invention to increase its bioavailability. Oral administration is one of the most commonly used routes of drug administration due to its ease of administration and high patient compliance and acceptability. However, oral administration can cause difficulties such as swallowing, choking, and nausea in geriatrics, pediatrics, bedridden patients, and patients with anxiety and panic disorders, leading to the development of alternative oral administration methods. Initially, to overcome swallowing difficulties, the idea of rapidly dissolving oral delivery systems and orally disintegrating thin films (strips) emerged in the late 1970s. It's also important to eliminate the psychological factors associated with swallowing tablets/capsules. Furthermore, conventional solid dosage forms (tablets, capsules) cannot be used without water. They are not suitable for use while traveling or when water is unavailable. Furthermore, a major disadvantage of these conventional dosage forms is that the pharmacological effects of the drug are not immediately apparent. The time it takes for the drug to reach the stomach and dissolve/disintegrate, resulting in the onset of pharmacological effects, typically takes 30-60 minutes at the earliest. In situations where immediate onset of pharmacological effects is desired, conventional tablets and capsules are inadequate. In conclusion, the deficiencies in the old technique/method are: J The absence of colchicine and febuxostat in any dosage form in the pharmaceutical market in combination, J The inability to obtain rapid and effective treatment with conventional drugs, J The possibility of more frequent and/or higher side and/or toxic effects due to the use of higher doses of conventional drugs, J The necessity to use these active ingredients separately in conventional dosage forms, J The low bioavailability of febuxostat when taken orally and therefore the need for high doses to show the desired effect, J The lack of new generation combination products that increase the comfort of life in gout patients, J The lack of a single product to prevent inflammation and pain as well as uric acid accumulation in gout patients. J Pediatric, geriatric individuals and some adults have difficulty swallowing or chewing solid dosage forms. These individuals are reluctant to take solid dosage forms (tablets, capsules) due to fear of choking, inability to provide personalized or lower-dose treatment with traditional dosage forms, economic disadvantage of taking two separate medications containing two active ingredients, inability to use conventional medications in situations where there is no access to water are among the significant deficiencies in the current method and/or technique. Description of the Invention In this description, oral thin film formulations containing colchicine and febuxostat nanocrystals for effective use in the treatment of gout, which were developed to provide rapid and effective treatment of pain and inflammation in gout disease as well as to increase comfort of life, are described in a way that does not create any limiting effect. The structural and characteristic features of the invention and all its advantages are described below. The present invention relates to oral thin film formulations containing colchicine and febuxostat nanocrystals together, which meet the above-mentioned requirements, eliminate all disadvantages and provide some additional advantages. The primary purpose of the invention is to provide a faster onset of action due to its oral thin film form, as well as to prevent inflammation and pain in gout patients and to prevent uric acid accumulation, enabling even dysphagic, geriatric, bedridden or mentally disabled patients to use their medications comfortably whenever and wherever they need, without the need to swallow or need water. Another purpose of the invention is to reduce the cost spent on two separate drugs by containing two drug active ingredients together. In order to achieve the above-mentioned objectives, this The invention includes oral thin-film dosage forms containing a combination of Febuxostat nanocrystals and Colchicine. This invention utilizes nanotechnology to reduce the water-insoluble Febuxostat to nanosize, enabling the use of this drug at a lower dose. The aim is to enhance the absorption and therefore bioavailability of both active ingredients, leveraging the advantages offered by this dosage form. Designed as an innovative dosage form (OTF) to facilitate patient compliance and accelerate pharmacological effects, this formulation will improve the quality of life and comfort of patients with premature ejaculation and erectile dysfunction. When examining dosage forms currently in use in the global pharmaceutical market, no pharmaceutical dosage form containing these two active ingredients simultaneously and offering a rapid onset of action is found in either our country's or the global pharmaceutical market, nor 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 high dose homogeneity and offer the best content uniformity among all oral dosage forms. Furthermore, tablets offer the most cost-effective production of all oral dosage forms. However, this method, which is difficult to implement for children and the elderly, has highlighted the need for a new oral medication form. Recent advances in technology have led to the development of alternative dosage forms, such as new-generation "Oral Thin Films" (OTFs), for patients who have difficulty swallowing solid dosage forms such as tablets and capsules (dysphagia). Today, the use of OTFs is increasing in many prescription and over-the-counter product groups, particularly for coughs, colds, sore throats, erectile dysfunction, allergic reactions, asthma, gastrointestinal disorders, hypertension, pain management, snoring, sleep problems, and multivitamin combinations. The pharmaceutical industry continues to convert conventional medications to OTFs. This new-generation dosage form aims to eliminate the psychological factors associated with using tablets/capsules for patients of all ages who experience dysphagia. Furthermore, its water-free use makes it easy to administer the medication even during travel or when water is unavailable. A key advantage of this dosage form is the immediate onset of the drug's pharmacological effects. Our formulations will offer the advantage of combining Febuxostat nanocrystals and Colchicine in a thin-film formulation. This dosage form, which undergoes rapid distribution or dissolution in the mouth, particularly through the capillaries passing through the buccal and sublingual layers, will also allow the active ingredients to rapidly enter the bloodstream and initiate their pharmacological effects. Lower doses of Febuxostat nanocrystals may 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 absorption in the gastrointestinal tract. OTF systems are solid dosage forms that disintegrate/dissolve/disperse within 1 minute upon placement in the mouth and can be administered without chewing, swallowing, or water. OTFs are drug formulations a few microns thick, prepared using hydrophilic polymers, placed on or at the base of the tongue, and rapidly dissolve upon contact with saliva. The US Food and Drug Administration (FDA) defines OTF as a flexible, non-fragile strip containing one or more active ingredients that, when placed on the tongue, dissolves/disintegrates quickly in saliva before passing into the gastrointestinal tract. OTFs have many unique advantages. Among these: J They are practical, J They exhibit improved stability for pH-sensitive drugs, J They can be used safely even in situations where access to water is not possible (such as travel), J There is no risk of choking, J They exhibit improved stability, J They are easy to administer, J They allow for easy administration to mentally unstable patients, J They leave little or no residue in the mouth after administration, J They bypass the gastrointestinal tract, thus improving bioavailability of drugs, J They allow for low-dose drug administration, thus reducing the incidence of side effects, J They provide more accurate dosing than liquid dosage forms, J They leave a pleasant mouth feel, J They ensure rapid onset of pharmacological effects in situations requiring emergency intervention, J They increase the rate and extent of drug absorption, J They provide a large surface area, especially when rapidly dissolving they provide improved bioavailability for less water-soluble drugs, J They do not hinder normal functions such as speaking and drinking, J Administration of drugs with a high risk of degradation in the gastrointestinal system, J They have an expanding market and product variety, They can be developed and launched in 12-16 months, J Being applicable to water-insoluble hydrophobic drugs and increasing their bioavailability. With the invention in order to overcome the deficiencies and/or disadvantages of the current situation, combining OTF dosage form with nanoparticulate drug delivery systems; accelerating pharmacological activity; increasing bioavailability; creating the desired effect at a lower dose by skipping the first pass effect seen in oral use of the drug; thus, significantly reducing possible side effects in the body; Among the innovations introduced are reducing formulation costs by reducing the amount of active ingredient used and facilitating patient access to medication. Consequently, new-generation OTF formulations have been developed to combine two active ingredients commonly used in gout disease into a single, combined drug form. This combination accelerates pharmacological action. It reduces the burden on the gastrointestinal system and minimizes side effects in patients with comorbidities. It addresses the economic disadvantages of administering two medications separately. It also provides an alternative dosage form for patients with difficulty swallowing solid dosage forms or those with mental health issues. It allows for safe medication administration even when water is unavailable. Most importantly, it develops a new drug delivery system that will improve the quality of life of gout patients. Thus, colchicine and febuxostat have been formulated together in a single dosage form for the first time. The invention, which is in the form of an oral thin film, is placed on the tip or base of the tongue and wetted by saliva within 30-60 seconds. In this way, the active ingredients contained in the film are released, dispersed and/or dissolved for local and/or systemic absorption. The invention has enabled the preparation of pharmaceutical dosage forms that simultaneously contain both active ingredients and offer a rapid onset of action. All excipients used in the formulation developed with the invention are water-soluble or dispersible. Febuxostat has been used in nanocrystalline formulations in the presence of surfactants Poloxamer 188 and Sodium Lauryl Sulfate (SLS). In other words, when these prepared OTFs are placed sublingually or at the tip, they dissolve very quickly with saliva. This allows for rapid onset of action, eliminating the need for water and eliminating swallowing difficulties. This allows for both a rapid onset of action and rapid resolution of patient complaints. Because the sublingual 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. Since absorption from the gastrointestinal tract is bypassed, the first-pass effect through the liver is eliminated. This rapid bioavailability stems from bypassing the first-pass effect and better permeability. Furthermore, the large surface area for absorption and ease of administration make oral administration a more effective method for systemic drug delivery. It makes the mucosa a very effective and selective way. In this way, it prevents inflammation and pain in gout patients as well as uric acid accumulation in a short time, and these drugs can be easily taken in combination by placing them on or under the tongue without requiring water. The formulation developed in the preferred embodiment of the invention preferably contains at least one excipient listed below in accordance with the amounts given in Table 1 and Table 2: Gelatin, Pullulan, Pectin, Sodium alginate, Polymerized resin, Maltodextrin, Hydroxy propyl methyl cellulose (HPMC), HPMC E 15, HPMC E 50, HPMC K100, Hydroxy ethyl cellulose (HEC), Carboxy methyl cellulose (CMC), Sodium carboxy methyl cellulose (NaCMC), Methyl cellulose (MC), Agar Agar, Xanthan gum, Gum Arabic, Carnauba wax, Crosspolymer linked acrylic acid polymer (at least one natural polymer selected from the group comprising Carbopol 980, 6000 or a combination thereof (more preferably a combination of NaCMC, Sodium alginate and Pectin); Gelatin, Pullulan, Pectin, Sodium alginate, Polymerized resin, Maltodextrin, Hydroxy propyl methyl cellulose (HPMC), HPMC E 15, HPMC E 50, HPMC K100, Hydroxy ethyl cellulose (HEC), Carboxy methyl cellulose (CMC), Sodium carboxy methyl cellulose (NaCMC), Methyl cellulose (MC), Agar Agar, Xanthan gum, Gum Arabic, Carnauba wax, Cross-linked acrylic acid polymer (at least one natural polymer selected from the group comprising Carbopol 980, 6000 or a combination thereof (more preferably a combination of Pullulan, Sodium alginate and Pectin); At least one elasticizer selected from the group comprising Glycerol, Propylene glycol, Sorbitol solution (50%, 60% or 70%), PEG 800, PEG 400 PEG 300 or a combination thereof and providing flexibility of the film (more preferably a combination of Glycerin or Propylene glycol); At least one saliva secretion agent selected from the group comprising Citric acid, Ascorbic acid, Lactic acid or Tartaric acid (more preferably Citric acid); At least one surfactant selected from the group comprising Isopropyl myristate or a combination thereof and used in the preparation of Febuxostat nanocrystals (more preferably Poloxamer ; 407, Poloxamer 188, Lecithin, Ethyl oleate or Isopropyl myristate or a combination thereof and provided surface activity in the preparation of OTF). preferably Tween 80); J At least one sweetening agent (more preferably Mannitol) selected from a group comprising Sucrose, Sorbitol, Lactose, Mannitol, XyIisorb, Maltodextrin or a combination thereof; J At least one superdisintegrant (more preferably Sodium starch glycolate) selected from the group comprising Korscarmellose 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, which ensures rapid disintegration of the film; J At least one flavouring agent (more preferably Sodium starch glycolate) selected from a group comprising Vanillin, Caramel, Neroli, Eucalyptol, Mint, Orange, Cinnamon or Chocolate flavour; preferably J At least one preservative selected from the group comprising sodium benzoate, potassium sorbate, propyl paraben, methyl paraben, sodium metabisulfite, sodium sulfite, benzyl alcohol, chlorbutanol or a combination thereof and providing protection of thin films from microorganisms (more preferably sodium benzoate); J Contains ultrapure water or aromatic water. Ingredient Name Available amount by weight (%) Febuxostat 1.0-20.0 Colchicine 0.01-5.0 Pectin 1.0-15.0 Sodium Carboxy Methyl Cellulose Sodium alginate 1.0-20.0 Sodium saccharin 1.0-15.0 Glycerin 2.5-20.0 Sodium starch glycolate 0.5-20.0 Citric acid 0.1-10.0 Sodium benzoate 0.5-10.0 Mannitol 0.1-5.0 It has no effect on the weight since it is vaporized using ultrapure water or aromatic water. Ingredient Name Usable amount by weight (%) Febuxostat 1.0-20.0 Colchicine 0.01-5.0 Pectin 1.0-15.0 Sodium alginate 1.0-20.0 Sodium saccharin 1.0-15.0 Glycerin 2.5-20.0 Propylene glycol 0.5-20.0 Sodium starch glycolate 2.5-20.0 Citric acid 0.5-10.0 Sodium benzoate 0.1-5.0 Mannitol 5.0-40.0 It has no effect on the weight since it is vaporized using ultrapure water or aromatic water. The formulation developed in a preferred embodiment of the invention; Febuxostat, Colchicine, Pectin, Sodium Carboxy Methyl Cellulose (NaCMC), Sodium alginate, Sodium saccharin, Glycerin, Sodium starch glycolate, Tween 80, Citric acid, Sodium benzoate, Mannitol, Vanillin and Ultrapure water. In a preferred embodiment of the invention, the developed formulation contains Febuxostat, Colchicine, Pectin, Pullulan, Sodium alginate, Sodium saccharin, Glycerin, Propylene glycol, Sodium starch glycolate, Tween 80, Citric acid, Sodium benzoate, Mannitol, Vanillin and Ultrapure water. In an exemplary embodiment of the invention, the developed formulation is prepared by following the following process steps: Poloxamer 188, SLS and ultrapure water are weighed into a vial on a precision balance with a sensitivity of at least 1 mg for febuxostat nanocrystals. For the organic phase, Febuxostat and ethyl alcohol are weighed. The organic phase is added dropwise to the water phase using a 22G syringe on a multipoint magnetic stirrer at 750 rpm. At the end of the dripping, homogeneous mixing is achieved for an additional 5 minutes. Vortexing is performed for 1 minute (2500 rpm). To remove the organic phase, evaporation is performed under vacuum (using a rotovapor) at 45°C for 5 minutes. The resulting mixture is sonicated again for 3 minutes at 60% power in cycle 2. Febuxostat nanocrystals are obtained during this process. For OTFs, all components of the formulation are weighed on a precision balance with a precision of at least 1 mg; the weighed components are preferably stirred in ultrapure water at 750 rpm for 2-4 hours. (preferably 1 mL for 1 film formulation); mixing at 750 rpm on a magnetic stirrer set at 20-60 ° C (preferably 40 ° C) during the last 5 minutes of mixing, heating and dissolving all components including the active ingredients; pouring the hot-molded mixture into molds so that each film contains equal amounts of Febuxostat nanocrystals and Colchicine; drying the mixture poured into the mold for preferably 6-72 hours (preferably 24 hours) at room temperature (preferably 25 ° C); storing each film in separate zip-lock bags, away from moisture, heat and light, at room temperature (25 ° C) until use.

Claims (1)

1.