TR201807398A2 - New Dosage Form - Google Patents

Abstract

The invention provides 1- (butan-2-yl) -4- (4- (4- (4 - ((2- (2,4-dichlorophenyl) -2-) 1H-1,2,4-triazole) as active ingredient. -1-ylmethyl) -1,3-dioxolan-4-ylmethoxy) phenyl) piperazin-1-yl) phenyl) -4,5-dihydro-1H-1,2,4-triazol-5-one, refers to a stable pharmaceutical dosage form which may be used as a solid / suspension.

Description

specification New Dosage Form triazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazin-1-yl)phenyl)-4,5-dihydro-1H- containing, solid and suspension It relates to a stable pharmaceutical dosage form that can be used as

CQcefoooOochsh State of the art API I is a broad spectrum triazole antifungal. Effect of other azole derivatives like antifungals, by inhibiting the synthesis of ergosterol in the membrane of the fungal cell shows. Because it does this by inhibiting the cytochrome P450 3A4 isoenzyme, in this way May increase plasma levels of metabolized drugs. BCS (biopharmaceuticals classification system), according to Class 11 (low resolution, high permeability) category.

API 1 is extensively metabolized in the liver. 40% of the dose as inactive metabolites via the urine, approximately 3-18% by the fecal route, less than 0.003% by the renal route. is discarded. The most important metabolite is hydroxyitraconazole. Hydroxytraconazole, in vitro It is an active metabolite with antifungal effect comparable to API I. Biological plasmina level in the environment is 2-3 times higher than API F.

API 1 is 99.8% bound to plasma proteins (especially albumin). significantly Mushrooms are also found in muscle, kidney, bone, stomach, spleen, lung and liver tissues. It accumulates in the skin, nails and vagina, which are prone to infections. cerebrospinal fluid, It is also found in very small amounts in body fluids such as tears and saliva. visible dispersion Its volume is 10.7 L/kg, and its total clearance is 5.1 mL/kg. Its elimination is more than systemic circulation. As it occurs due to epidermal regeneration, drug level persists for 1-4 weeks after discontinuation of therapy.

The bioavailability of API I is 55%. Bioavailability of intake immediately after meals is increasing. In fasting and satiety conditions, 50-200 mg doses were administered to 6 male healthy volunteers. The results when API I capsule is given are as follows; Table 1. Results when API I capsules were given at doses of 150-200 mg (ngh/mL) A 2-fold increase in the dose increases the API I performance in plasma approximately 3-fold. Hunger A single dose of 200 mg API I capsule in 27 healthy male volunteers under and fed conditions. The results when given were as follows; Table 2. Results when given 200 mg API I capsules API I Hydroxytraconazole Steady-state concentrations are reached after 15 days of use at a dose of 50-400mg.

A single dose of 200 mg APl l capsules in 27 healthy male volunteers under fed conditions. the results given are as follows; API I Hydroxytraconazole There are 3 pharmaceutical forms of API I currently available. These are capsules (100mg, in hard gelatin capsules), oral solution (150 mL colored glass containing 10mg/mL API l) vials) and IV infusion kit (25mL colorless glass ampoule containing 10mg/mL API, pyrogen-free solution and 50mL bag containing 0.9% NaCl) forms.

Main; blastomycosis, histoplasmosis, aspergillosis (tolerating amphotericin B treatment) In the treatment of patients who cannot in onychomycosis, its oral solution also in oropharyngeal/esophageal candidiasis and intravenous Empirical evaluation of febrile neutropenic patients with suspected primary infection used in the treatment.

100-400 mg daily depending on the type of infection (in systemic fungal infections) A 3-day loading dose of 600 mg per day is recommended) 7 days to 1 year treatment may be required.

Since API l is an ionizable substance in an acidic environment, it should be taken with cola drinks. increases absorption. Conversely, antacids, H2 receptor antagonists (such as famotidine, cimetidine, ranitidine) or proton pump inhibitors such as omeprazole It has been determined that absorption decreases as it raises the stomach pH.

Current studies include conventional microsphere/micropellet solid dispersions of API Fin. It is aimed to increase the solubility and the effect in this way by putting it into the form. made In studies, solid dispersions and self-emulsifying systems of API Iain Solubility and bioavailability were increased by preparing the No study was found regarding the dosage form. The formulation subject to the invention, A drug dosage form and combination that is not available in Turkey and in the world. covers. relates to tablets and a method of preparation thereof.

In the patent number EP0904060, API Pin is coated with hydroxypropyl methyl cellulose and sugar. The preparation of micropellets is protected by patent. To provide fluidity and strength and to improve API Pin bioavailability, API I It provides an ultra-micro capsule containing formulation and efficient manufacture of a pellet to improve its solubility. By doing this, the stability, solubility and treatment of API 1 were improved. However this application also differs from the method in this invention.

Superficial such as tinea corporis, tinea cruris, tinea pedis, tinea manum, pityriasis versicolor infections with aspergillosis, blastomycosis, histoplasmosis, esophageal, oropharyngeal and vulvovaginal candidiasis, cryptococcosis, coccidiomycosis, chromomycosis, onychomycosis, in the treatment of systemic fungal infections such as paracoccidiomycosis, sporotrichosis The micropellet capsule formulation used is known.

Technical problems that the invention aims to solve In the current application, by increasing the solubility, the drug in the classical micropellet form is injected into the stomach. reach is provided. However, in this case, it comes from the upper (proximal) region of the intestine. Since the absorption window is narrow, it cannot be absorbed sufficiently. In this invention in the stomach In order to prolong the absorption time by increasing the residence time and increase the absorbed amount, By preparing a floating dosage form that can remain for a long time, its absorption and thus bioavailability was increased. With the development of this invention, its absorption is only From the absorption window for API I from the proximal (upper) region of the small intestine no contribution to bioavailability after removal is eliminated. Like this Thanks to this formulation, which reveals the tobacco content at stomach pH, API liin is controlled. In a way, it was ensured that it was completely absorbed from the proximal region. As a result; optimizing bioavailability, both preventive and therapeutic efficacy using a pharmaceutical dosage form that has a long shelf life, increases patient compliance is intended to present.

Description of the invention In this invention, API Pin, a substance with antifungal effect and bioavailability problem. by preparing the floating microspheres/beads that are held in the stomach for a long time and Bioavailability is increased by increasing its absorption from the proximal region where specific absorption occurs. is intended to increase. For this purpose, gas forming agent by ionotropic gelation method. Microsphere/bead formulations containing no microspheres were prepared.

Microspheres/beads are the crosslinker of a solution of chitosan containing API I in acetic acid. It was obtained by dripping into a solution containing tripolyphosphate. swimming feature here, by the matrix that swells on contact with the air and gastric juice trapped in the microcure/bead has been provided. Since API Fin has low solubility in pH 1.2 environment In order to increase the solubility in microspheres/beads, the active substance should be randomized. Complexes prepared with methylated beta cyclodextrin were used.

As a result, considering particle sizes, release properties and surface properties, The most suitable formula for the purpose was selected and API Pin was used in cell culture studies with this formula. The permeability of the formula is increased and the in vivo imaging studies of the formula It was determined that it remained in the stomach for the duration (6.5 hours).

Detailed description of the invention: Controlled release systems maintain the blood concentration of the active substance for the desired period of time. They are dosage forms that keep them at the desired level. This term refers to the localization of the active substance to the desired area. It can also be used for dosage forms that provide administration and targeting.

One of the controlled release drug systems, the duration of stay in the gastrointestinal tract prolonging systems are generally high-density systems, floating dosing systems, sisen and expanding systems, superporous hydrogel systems, mucoadhesive and bioadhesive systems and magnetic systems. The floating dosing system in this invention used.

In single-unit systems, swelling feature when in contact with gastric fluid in dosage form hydrophilic polymers (such as HPMC, EC, NaCMC, alginic acid) It is used if the density is less than 1” and the dosage form floats in the stomach for a long time. retention is ensured. Meanwhile, active substance release by dilution from the hydrated layer is taking place. In such systems, large amounts of active substance are released in the GI tract. There may be irritation depending on the reliability and repeatability problems may occur. For multi-unit systems, They are systems that prevent sudden dose increases and reduce changes in absorption. Albumin, This product, in which various polymers such as gelatin, starch, polymethacrylate, polyacrylamine are used. systems with an effervescent part and systems without an effervescent part. is separating.

Microspheres are particles of the active substance at the molecular level or macroscopically. It has a diameter distribution ranging from a few μm to mm. solid, spherical, particulate dosage forms with controlled release drug can be prepared as carrier systems. in the dosage form prepared in this invention. Because particulate structures have a particle size greater than 1 mm (~2 mm) use is deemed appropriate.

In this invention, with the dosage form prepared in the form of floating beads, the dosing frequency is reduced. increased patient compliance, increased bioavailability, retention of the dosage form in the stomach to increase the duration of the drug, to release the active substance in a controlled manner within the extended period, the ability to release the active substance to a certain region (stomach) and Irritation can be prevented.

In this invention, first of all, the UV and IR spectrum of the active substance, DSC analysis, melting point determination has been made and its accuracy has been proven by references. pH, which is then the stomach environment Solubility determination in 1,2 and short-term stability studies in this solvent were carried out.

IR spectrum, DSC analysis, melting point determination and viscosity determination of the selected polymer has been made. In addition, after the solid dispersion of API Fin with RAMEB is formed, the above By repeating all the analyzes given, a solid dispersion of active substance solubility It has been confirmed that it is increased with the formation of In this invention, beads are used by the ionotropic gelation method. It was prepared with API I-RAMEB complexes using IR of the prepared beads spectrum, DSC analysis, SEM analysis, particle size and dispersion analyses, effective substance quantification (UV, HPLC) and process efficiency and dissolution rate determinations were made, swimming start and swimming times were determined.

With the ideal formulation, first cell culture studies were carried out, then capsules were added. filled and in vivo studies were started. 100mg API I with randomized methylated beta cyclodextrin (RAMEB) (1 :2 molar ratio) 3% polyethyleneglycol was added to the formed complex, has been obtained. Then, the inner phase was added to aqueous solutions containing 1% w/v tripolyphosphate (TPP), 0.45 With the help of a mm diameter insulin injector, the rate was added to be 30 drops/minute. 2 After one hour reaction time, the beads were separated by filtration and rinsed with distilled water. has been washed. The separated beads were finally dried in a lyophilizer for 48 hours.

Formula API I:RAMEB -PEG 4000 Chitosan Acetic acid TPP code (1:2) solution Permeability (cm/sec) In cell culture studies using Caco-2 cells, the absorption of the active substance starting from the proximal region where the small intestine meets the stomach, In order to observe the pH-dependent permeability changes in different regions, 3 It has been studied at different pH7 (pH 5, 6 and 7.4). Both the pure active ingredient and the ideal formula In the permeability findings of the NG17 coded formula, which is thought to be When API 1 is applied, the permeability value of 3.04E-06 cm/sec is determined by the application of the NG17 formula. It was found that it increased to 5.88E-06 cm/sec. The same increase is in the thin layer around pH 6-7. It was also seen in the middle part of the intestine (jejunum) and when pure API l was applied to the cells. It was determined that it increased in cm/snaye. In the last part of the small intestine (ileum), which has a pH around 7-8 If the perineability value of 5,62E-06 cm/sec belonging to pure API II, the NG17 formula is applied. It was observed that it decreased slightly to 4.77E-06 cm/sec. From the findings As will be understood, a solution containing API I:RAMEB complex and 3% PEG 4000 in a molar ratio of 1:2. The formulation with the code NG17 is at pH 5, which is the pH of the absorption region of API I. increased its permeability.

Formulations labeled with technetium-99m (”mTc) were tested on rabbits and It was determined that the ideal formula remained in the ini for 6.5 hours in the determinations made by gamma scintigraphy. has been made. In in vivo studies in rabbits, the NGl7 formulation was not studied. gamma scintigraphy images showing that it floats in the stomach for a period of 6.5 hours It is shown in figure ls.

In this invention, increasing patient compliance and bioavailability by reducing the dosing frequency. has been provided. As the observed side effect decreased, the active substance used in the unit dosage form amount has also decreased.

Claims (1)

CLAIMS triazol-1-ylmethyl)-1,3-dioxolan-4-yl)n1ethoxyylphenyl)piperazin-1-yl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-5-one It is a composition containing, Feature; It is a dosage form prepared with floating beads. . It is the dosage form according to claim 1; Its feature is that it is a bead formulation that does not contain gas-forming agents with the ionotropic gelation method. . It is a bead formulation according to claim 2, its feature is; Besides PEG 4000, it is complexes prepared with randomized methylated beta cyclodextrin. . It is a formulation according to claim 3 and its feature is; It is the use of chitosan as the polymeric (matrix) structure that controls the output of the active substance. . It is a dosage form according to the request, and its feature is; It is used in hard gelatin capsule or sachet form. . It is a dosage form according to claim 2, and its feature is; It is used in the treatment of fungal diseases.