Maropitant formulation

Abstract

The invention relates to a pharmaceutical composition comprising an aqueous solution containing 8 mg / mL to 12 mg / mL of maropitant or 12 mg / mL to 16 mg / mL of a pharmaceutically acceptable salt thereof, 55 mg / mL to 70 mg / mL of sulfobutylether β-cyclodextrin and 18 mg / mL to 30 mg / mL of N-butanol, its use and a method for producing the pharmaceutical composition comprising the steps of: (i) adding sulfobutylether β-cyclodextrin and maropitant, in particular maropitant citrate monohydrate, to water to obtain an aqueous solution, (ii) dissolving maropitant, in particular maropitant citrate monohydrate, in the aqueous solution, (iii) adding N-butanol to the solution and (iv) optionally adjusting the pH to a value between 3.5 and 5.5, in particular 4.0 to 5.0, preferably 4.3 to 4.7, by adding a pharmaceutically acceptable base or acid to the aqueous solution.

Description

[0001] MAROPITANT FORMULATION

[0002] The present invention relates to a pharmaceutical composition comprising maropitant, a process for preparing the pharmaceutical composition and its use as a medicament, in particular for the prevention and treatment of nausea and vomiting in mammals, in particular dogs and cats.

[0003] Maropitant is a highly selective NK-1 receptor antagonist. It is a weak base and lipophilic drug belonging to the quinuclidine class. Maropitant is used as a veterinary drug.

[0004] NK1 receptors for substance P are widely distributed in body cells. They are found in the central and peripheral nervous system of mammals, the digestive tract, the circulatory system, hematopoietic and inflammatory and / or immune response cells, and the vascular endothelium. Several biological processes are known to be involved in the regulation of NK1 receptors.

[0005] NK-1 receptor antagonists prevent substance P, an important neurotransmitter involved in vomiting, from binding to neurokinin-1 receptors and block NK-1 receptors in the central nervous system. These receptors are located on the surface of cells in the part of the brain that controls nausea and vomiting. When substance P binds to these receptors, nausea and vomiting result. By inhibiting the receptors, NK-1 receptor antagonists can prevent, reduce, or prevent nausea and vomiting.

[0006] Other known NK-1 receptor antagonists besides maropitant are aprepitant and fosaprepitant. They belong to the group of antiemetics and are commonly used in human medicine as part of chemotherapy.

[0007] EP587723B describes quinuclidine derivatives, pharmaceutical compositions comprising such compounds, and the use of such compounds in the treatment and prevention of inflammatory diseases and diseases of the central nervous system, as well as several other diseases.

[0008] EP773026A relates to the use of NK1 receptor antagonists for the treatment of cancer in mammals. EP1713504B1 describes the use of 10 mg / mL maropitant citrate in combination with 61 to 72 mg / mL sulfobutyl ether-ß-cyclodextrin and 3.2 to 4.2 mg / mL meta-cresol for the treatment of emesis and to improve recovery after anesthesia. Following subcutaneous injection, a mild to moderate pain reaction may occur, particularly with formulations containing the preservative metacresol. In cats, administration may lead to mineralization of subcutaneous infiltrates.

[0009] EP3173071B1 discloses a pharmaceutical composition containing maropitant citrate, a pharmaceutically acceptable β-cyclodextrin, and 7-18 mg / mL phenylmethanol. Here, too, transient pain reactions at the injection site are observed upon subcutaneous administration.

[0010] The object of the present invention is to provide a pharmaceutical composition for the treatment of nausea and / or vomiting and a process for its preparation, where local reactions, in particular pain reactions, of the animals at the injection site are reduced or even eliminated.

[0011] This object is achieved by the pharmaceutical composition according to the invention and a process for producing this pharmaceutical composition as well as the use of this pharmaceutical composition according to the claims.

[0012] The object of the invention is achieved independently by a pharmaceutical composition and a process for producing the pharmaceutical composition.

[0013] The pharmaceutical composition comprises an aqueous solution containing 8 mg / mL to 12 mg / mL maropitant or 12 mg / mL to 16 mg / mL of a pharmaceutically acceptable salt thereof, 55 mg / mL to 70 mg / mL sulfobutyl ether-ß-cyclodextrin, and 18 mg / mL to 30 mg / mL n-butanol. The advantage of this pharmaceutical composition is that no or very little pain occurs at the injection site according to the visual analogue scale (VAS) and simple descriptive scale (SDS), thus resulting in a very high injection tolerance. The VAS and SDS scores for the composition according to the invention are lower than those for a comparable preparation known from the prior art. In addition, the antimicrobial effect of N-butanol in the composition according to the invention containing maropitant and sulfobutyl ether-ß-cyclodextrin is extremely good.

[0014] N-butanol is preferably present in a concentration of 20 mg / mL to 25 mg / mL, in particular 21 mg / mL to 24 mg / mL, preferably 22 mg / mL, which, on the one hand, allows good tolerance at the injection site to be achieved, but, on the other hand, prevents complex formation with the solubilizer sulfobutyl ether-ß-cyclodextrin, and therefore no inactivation of the preservative N-butanol. It has been shown that N-butanol as a preservative in the pharmaceutical composition according to the invention is significantly better tolerated at the injection site than commercially available injectable maropitant compositions.

[0015] With the pharmaceutical composition according to the invention containing N-butanol, statistically significantly lower values ​​are measured and observed for both the VAS observation and the SDS observation.

[0016] The pharmaceutically acceptable salt of maropitant is preferably maropitant citrate monohydrate and is available at a concentration of 13.5 mg / mL to 15.5 mg / mL, preferably 14.48 mg / mL, which provides optimal antiemetic efficacy in mammals, particularly dogs and cats. The active ingredient is primarily used for the prophylaxis and treatment of acute vomiting caused by central and peripheral toxins, e.g., during or shortly after surgery or to improve recovery from general anesthesia.

[0017] Sulfobutyl ether-ß-cyclodextrin is present in a concentration of 60 mg / mL to 65 mg / mL, preferably 63 mg / mL, to achieve sufficient solubility of maropitant in the pharmaceutical composition. Sulfobutyl ether-ß-cyclodextrin has been shown to improve the solubility of maropitant. Sulfobutyl ether-ß-cyclodextrin is polyanionic and interacts particularly well with maropitant at this concentration. Furthermore, the selected concentration range of sulfobutyl ether-ß-cyclodextrin achieves exceptional solubility and parenteral safety. The aqueous solution according to the invention is free of other solvents that could potentially reduce injection tolerance.The pharmaceutical composition has a pH between 3.0 and 6.0, in particular between 4.0 and 5.0, preferably between 4.3 and 4.7, in order to be within a pharmaceutically acceptable range compatible with parenteral administration, in particular subcutaneous injection.

[0018] The specific density of the pharmaceutical composition is between 1.010 g / cm 3 and 1,040 g / cm 3 , in particular 1.015 g / cm 3 and 1,030 g / cm 3 , preferably between 1.021 g / cm 3 and 1.025 g / cm 3 . The specific density forms part of the finished product specification for the pharmaceutical composition according to the invention in the form of an aqueous solution.

[0019] Another aspect of the present invention relates to a pharmaceutical composition for use as a medicament. The composition according to the invention is clinically useful for the prevention and treatment of nausea and vomiting in mammals, particularly dogs and cats.

[0020] In one embodiment, the pharmaceutical composition according to the invention is administered parenterally by injection or infusion. For example, the pharmaceutical composition can be administered intravenously, subcutaneously, and intramuscularly. Preferably, the pharmaceutical composition according to the present invention is administered subcutaneously or intravenously. The present invention has the advantage that the composition according to the invention results in only a minimal pain response, if any, as determined on a 10 mm visual analog pain scale or a descriptive pain scale.

[0021] Furthermore, it proves to be advantageous that a multi-dose container comprises a pharmaceutical composition according to the invention, whereby preservation is absolutely necessary for multi-dose containers.

[0022] In a further aspect, the present invention relates to a process for preparing a pharmaceutical composition as defined above, comprising the steps of:

[0023] (i) adding sulfobutyl ether-ß-cyclodextrin and maropitant, in particular maropitant citrate monohydrate, to water to obtain an aqueous solution, (ii) dissolving maropitant, in particular maropitant citrate monohydrate, in the aqueous solution,

[0024] (iii) adding N-butanol to the solution and mixing the composition and

[0025] (iv) Adjusting the pH to a value between 3.5 and 5.5, in particular 4.0 to 5.0, preferably 4.3 to 4.7, by adding a pharmaceutically acceptable base or acid to the aqueous solution. The process according to the invention for producing the pharmaceutical composition enables optimal adaptation of the production process to the product to be produced, without optimizing the production process economically and yet without compromising the composition's requirements.

[0026] For a better understanding of the invention, it is explained in more detail using the following figures.

[0027] Fig. 1 Results of the visual analogue scale (VAS) of observers 1 and 2;

[0028] Fig. 2 Visual analogue scale (VAS) results in relation to days of administration and injection sites;

[0029] Fig. 3 Simple descriptive scale (SDS) results of the test formulation (M-BA) and the reference formulation (MM).

[0030] The present invention relates to a pharmaceutical composition comprising an aqueous solution containing maropitant or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable sulfobutyl ether-ß-cyclodextrin, and N-butanol as a pharmaceutically acceptable preservative.

[0031] Specifically, the pharmaceutical composition of the invention comprises an aqueous solution containing 8 mg / mL to 12 mg / mL of maropitant or 12 mg / mL to 16 mg / mL of a pharmaceutically acceptable salt thereof, 55 mg / mL to 70 mg / mL of sulfobutyl ether-ß-cyclodextrin and 18 mg / mL to 30 mg / mL of N-butanol.

[0032] The concentration of N-butanol in the pharmaceutical composition is a value selected from a range of 18 mg / mL to 30 mg / mL, or 20 mg / mL to 25 mg / mL, in particular 21 mg / mL to 24 mg / mL, preferably 22 mg / mL.

[0033] N-Butanol, also known as 1-butanol, propyl methanol, butyl alcohol, or butyl hydroxide, is a chemical compound from the alkanol group. An important factor in the development of the pharmaceutical composition according to the invention as a formulation for parenteral administration is the determination of a suitable preservative system. Various classes of preservatives were tested for their suitability for use in the formulation according to the invention. An overview of the tested substances is shown in Table 1 below. They are assigned to the following substance classes: benzoates, phenols, quaternary ammonium salts, and alcohols with molecular weights between 74.1 and 448.1 g / mol.

[0034] Table 1: Tested substances as preservatives Samples were prepared on a laboratory scale, and all samples were tested for their preservative effect according to Ph. Eur. II, Chapter 5.1.3-1. The European Pharmacopoeia (Ph. Eur.) is the reference work for the quality control of medicinal products in Europe. The pharmaceutical composition according to the invention must comply with the standards of Ph. Eur. If a pharmaceutical preparation does not possess sufficient antimicrobial activity on its own, antimicrobial preservatives can be added, particularly in aqueous preparations, to limit microbial contamination that could occur in a product under normal storage and use conditions, especially in multi-dose containers, and pose a risk to the patient through infection and / or deterioration of the preparation.According to the European Pharmacopoeia, preservatives are mandatory for injectables when they are contained in multi-dose containers or when they were manufactured under aseptic conditions but cannot be sterilized in their final, sealed single-dose containers. The aim will always be to avoid preservatives because complications associated with their use are known. However, preservatives are essential for multi-dose containers. In a preferred embodiment, the pharmaceutical composition according to the invention is contained in a multi-dose container.

[0035] The test consists of preparing the formulation with a prescribed inoculum of suitable microorganisms, storing the formulation at a prescribed temperature, taking a sample of the formulation at specified intervals, and counting the organisms in the samples thus taken.

[0036] The monograph requires compliance with criterion A for medicinal products intended for parenteral use. The A criteria specify the desired efficacy. In justified cases where these A criteria cannot be met, e.g., due to an increased risk of adverse reactions, only the B criteria need to be met.

[0037] The criteria for evaluating antimicrobial activity are given in Table 1 in the form of the logarithmic reduction in the number of viable microorganisms compared to the value obtained for the inoculum.

[0038] Table 2: Microbial activity nf: not detectable kS: no increase

[0039] The A criteria express the recommended effect to be achieved. In justified cases where the A criteria cannot be met, for example, due to an increased risk of side effects, the B criteria must be met.

[0040] The acceptance criteria for the pharmaceutical composition according to the invention correspond to those in Table 5.1.3.1 of Eu. Pharm. 8.0.

[0041] First, the various preservative systems commonly used in parenteral formulations were tested for their preservative efficacy in combination with the solubilizer sulfobutyl ether-ß-cyclodextrin (SBECD). The aim was to determine whether SBECD has a negative impact on the preservative efficacy of the respective substances. Samples of combinations of SBECD with various preservatives were produced on a laboratory scale. The various preservative systems were used at specified concentrations, and the solubilizer SBECD was used at a concentration suitable for dissolving the active pharmaceutical ingredient maropitant citrate monohydrate. The first samples were placebo solutions without the active pharmaceutical ingredient maropitant.Laboratory samples A-E contain the preservatives methyl p-hydroxybenzoate and propyl p-hydroxybenzoate, benzyl alcohol, chlorocresol, benzethonium chloride, and benzalkonium chloride. Only the sample containing benzyl alcohol meets criterion A in the preservative efficacy test. The other preservatives were also used at proven concentrations, but the presence of SBECD in the solution hampered the preservative efficacy of these substances.

[0042] The benzyl alcohol concentration of 20 mg / mL in laboratory sample B is known from EP1713504B1 in a pharmaceutical formulation containing maropitant. It was further investigated whether a lower concentration than 20 mg / mL of benzyl alcohol in combination with SBECD would achieve a suitable preservative effect, as some parenteral preparations on the market contain lower concentrations of benzyl alcohol. However, in combination with SBECD, the preservative effect of lower benzyl alcohol concentrations was insufficient, as was observed, among other things, in laboratory sample B2.

[0043] In addition, combinations of various preservatives were tested. Laboratory samples F1, F2, and G contain combinations of benzyl alcohol, propylene glycol, and n-butanol. Surprisingly, both samples containing n-butanol meet criterion A of the preservative efficacy test. The sample containing propylene and benzyl alcohol fails the test.

[0044] Therefore, further testing was conducted to determine whether n-butanol alone could be responsible for the preservative effect in laboratory samples F1 and F2. To confirm this, laboratory samples containing n-butanol as a preservative were prepared. Both samples, BO and W, meet criterion A according to Ph. Eur. 5.1.3-1. While laboratory sample BO is a placebo sample without the active pharmaceutical ingredient, laboratory sample W contains the active ingredient maropitant citrate monohydrate. These results surprisingly demonstrate that a formulation of maropitant citrate monohydrate with n-butanol as a preservative and SBECD as a solubilizing agent meets the criteria for antimicrobial preservative effect of the European Pharmacopoeia for parenteral preparations. It can be demonstrated that the solubilizing agent SBECD does not impair the preservative effect of n-butanol in the concentration range used.

[0045] In order to meet the requirements of the Committee for Medicinal Products for Human Use (CHMP), formerly known as the Committee for Proprietary Medicinal Products (CPMP) Committee for Veterinary Medicinal Products CPMP / CVMP / QWP / 115 / 95, the need to add a preservative to the finished product at the selected concentration must be demonstrated. For this purpose, laboratory samples with different concentrations of N-butanol are prepared and tested. Samples with up to 20 mg / mL N-butanol met criterion A, while samples with 18 mg / mL N-butanol did not comply with the limit (Lab sample I). Therefore, a concentration of 20 mg / mL is set as the lower specification limit for N-butanol to meet criterion A. This concentration limit must be maintained throughout the intended shelf life and storage of the medicinal product. A 10% reduction in the preservative content is acceptable throughout the shelf life.Therefore, a nominal N-butanol concentration of 22 mg / mL in the finished solution of the pharmaceutical composition according to the invention is chosen as the most suitable. This is the lowest possible amount of preservative in the formulation that achieves a sufficient preservative effect. Considering the safety of the treated animal, an N-butanol concentration of 22 mg / mL is therefore the most favorable preservative concentration. On the one hand, this concentration ensures adequate preservation of the drug, even during its shelf life. On the other hand, the patient does not receive any avoidable amounts of preservative.

[0046] However, to meet only criterion B, a concentration of 18 mg / mL N-butanol in the pharmaceutical composition according to the invention is sufficient.

[0047] The preservative effect of n-butanol in a SBECD-containing solution is independent of the presence of the active pharmaceutical ingredient, as laboratory samples BO and W showed comparable preservative effects. Therefore, it is irrelevant for the preservation of the formulation whether the active pharmaceutical ingredient is used as a base (maropitant) or as a pharmaceutically acceptable salt thereof, e.g., maropitant citrate monohydrate.

[0048] The experiments show that many preservative systems commonly used in parenteral preparations are not suitable for use in a formulation containing the solubilizing agent SBECD. It can be shown that the preservative effect of these substances is blocked by SBECD when used in common concentrations. In contrast, the preservative effect of N-butanol is not hindered by SBECD, and the formulations achieve the required level of antimicrobial preservative effect. At a concentration of 22 mg / mL N-butanol, the pharmaceutical composition of the invention is sufficiently preserved without exposing the treated animal to unnecessarily high levels of the preservative.Overall, a formulation of 63 mg / mL SBECD and 14.48 mg / mL maropitant citrate monohydrate, equivalent to 10 mg / mL maropitant, is successfully preserved in aqueous solution by the addition of 22 mg / mL n-butanol.

[0049] The results of the antimicrobial preservative efficacy test are summarized in Table 3 below. Table 3: Antimicrobial preservative efficacy of different preservatives

[0050] The pharmaceutically acceptable salt of maropitant is preferably maropitant citrate monohydrate, the concentration of which is selected from a range with a lower limit of 12 mg / mL and an upper limit of 16 mg / mL, and preferably between 13.5 mg / mL and 15.5 mg / mL, and in particular 14.48 mg / mL.

[0051] Maropitant is preferably in the form of a pharmaceutically acceptable salt, e.g., citrate. Alternatively, the free base of maropitant can be used in combination with a citric acid solution.

[0052] Maropitant citrate monohydrate, which has a molecular weight of 678.81, can be used.

[0053] The concentration of sulfobutyl ether-ß-cyclodextrin in the pharmaceutical composition is a value selected from a range with a lower limit of 55 mg / mL and an upper limit of 70 mg / mL, in particular 60 mg / mL to 65 mg / mL, preferably 63 mg / mL.

[0054] In the composition according to the invention, the pharmaceutically acceptable sulfobutyl ether-ß-cyclodextrin is preferably sulfobutyl ether-ß-cyclodextrin sodium.

[0055] The pH of the pharmaceutical composition has a value of 3.0 to 6.0, in particular 4.0 to 5.0, preferably 4.3 to 4.7, and is adjusted if necessary with a pharmaceutically acceptable base or acid.

[0056] In one embodiment, the pharmaceutically acceptable base is sodium hydroxide, sodium bicarbonate, or ammonium hydroxide, preferably sodium hydroxide. It has been shown that there are no adverse side effects when sodium hydroxide is included in the composition according to the present invention.

[0057] In one embodiment, the pharmaceutically acceptable acid is selected from the group comprising hydrochloric acid, formic acid, acetic acid, and citric acid, preferably citric acid. It has been shown that both inorganic acids, e.g., hydrochloric acid, and organic acids, e.g., formic acid, acetic acid, and citric acid, can be used to adjust the composition to the desired pH between 3 and 6. Citric acid is preferably used because it also provides a source of citrate anions, which are the preferred anion, thus achieving good physiological tolerance and utilization.

[0058] The specific density of the pharmaceutical composition is between 1.010 g / cm 3 and 1,040 g / cm 3 , in particular 1.015 g / cm 3 and 1,030 g / cm 3 , preferably between 1.021 g / cm 3 and 1.025 g / cm 3 .

[0059] The pharmaceutical composition according to the invention is used as a medicament. It is administered for use in the treatment and prevention of nausea and vomiting in mammals, particularly dogs and cats.

[0060] Administration is particularly preferably parenteral by injection or infusion, whereby the pharmaceutical composition is preferably administered intravenously or subcutaneously, but oral administration or intramuscular administration is also possible.

[0061] The preparation of the pharmaceutical composition according to the invention comprises the steps:

[0062] (i) adding sulfobutyl ether-ß-cyclodextrin and maropitant, in particular maropitant citrate monohydrate, to water to obtain an aqueous solution,

[0063] (ii) dissolving maropitant, in particular maropitant citrate monohydrate, in the aqueous solution,

[0064] (iii) adding N-butanol to the solution and mixing the aqueous solution and

[0065] (iv) optionally adjusting the pH to a value between 3.5 and 5.5, in particular 4.0 to 5.0, preferably 4.3 to 4.7, by adding a pharmaceutically acceptable base or acid to the aqueous solution.

[0066] The aqueous medium is preferably water, but any other suitable medium may also be used.

[0067] The water may contain additional solvents, which may, for example, be adjuvants in the solution. Suitable solvents that can be used in the solution are known to those skilled in the art. However, an aqueous medium free of organic cosolvents is preferably used.

[0068] Mixing the above substances causes them to dissolve in the medium.

[0069] The substances are added to the medium in the order listed above. For step (i), sulfobutyl ether-ß-cyclodextrin is first added to water, mixed, and dissolved at room temperature with continuous stirring. Maropitant citrate monohydrate is then added to the aqueous solution to complex the maropitant cations and thus improve the solubility of the maropitant cations. Once maropitant citrate monohydrate is dissolved, a pharmaceutically acceptable n-butanol is added, and if necessary, the pH of the aqueous solution, in particular of the pharmaceutical composition, is adjusted to the desired pH between 3.0 and 6.0, in particular 4.3 to 4.7, by titration with a pharmaceutically acceptable acid or base.

[0070] A study compares the local pain response after subcutaneous injection of the pharmaceutical composition according to the invention with a maropitant formulation containing N-butanol compared to a maropitant formulation containing metacresol, administered to dogs at refrigerated temperatures (approximately 4°C) and at room temperature (approximately 25°C). Thirty-two healthy beagle dogs, eight per group, are administered four subcutaneous injections.

[0071] The test formulation (pharmaceutical composition according to the invention comprising a maropitant formulation with N-butanol) and the reference formulation (maropitant formulation with metacresol) are administered subcutaneously (sc) to beagle dogs.

[0072] Figure 1 shows the mean and standard deviation of the visual analogue scale (VAS) results in mm compared between observer 1 and observer 2. Statistically significant differences were found when comparing the geometric mean values ​​of the two observers for the visual analogue scale (VAS) between the test formulation and the reference formulation (p=0.003).

[0073] Figure 2 shows the mean and standard deviation of the visual analogue scale (VAS) results in mm comparing the administration stage and injection sites. No differences were observed with regard to administration times or sequences. No significant differences were observed with regard to temperature between 4°C and 25°C within the respective test and reference formulations. However, the test formulation was always less painful than the reference formulation.

[0074] Figure 3 shows the simple descriptive scale (SDS) results for the test formulation (M-BA) and the reference formulation (MM) with respect to temperature and observer. Statistically significant differences were also observed when comparing the medians of the two observers for the descriptive observations (SDS) between the test formulation and the reference formulation (p=0.004).

[0075] Examples

[0076] The maropitant citrate monohydrate, sulfobutyl ether-ß-cyclodextrin, and N-butanol required for the manufacture of the pharmaceutical composition meet the quality requirements for the manufacture of a veterinary medicinal product. The components of the pharmaceutical composition are used without further purification steps.

[0077] Examples 1 to 7

[0078] Examples 1 to 3 contain 63 mg / mL of sulfobutyl ether-ß-cyclodextrin in an aqueous medium, preferably water, and N-butanol or a combination of N-butanol and another preservative, such as benzyl alcohol or propylene alcohol, as a preservative. The active ingredient maropitant is not included.

[0079] In Examples 4 to 7, 63 mg / mL of sulfobutyl ether-ß-cyclodextrin is added to an aqueous medium, preferably water. Subsequently, 14.48 mg / mL of maropitant citrate monohydrate and n-butanol are added at varying concentrations. The formulation is titrated with sodium hydroxide and citric acid to obtain the optimal pH of 4.3 to 4.7.

[0080] In further examples of the pharmaceutical composition, 10 mg / mL of maropitant base and 4.1 mg / mL of citric acid are used instead of 14.48 mg / mL of maropitant citrate monohydrate. The remaining components, 63 mg / mL of sulfobutyl ether-ß-cyclodextrin and the preservative n-butanol, remain the same at the concentrations used in the table above. The pH is adjusted to a value of 4.4 to 4.7 with hydrochloric acid and sodium hydroxide.

[0081] It was shown that regardless of the maropitant source used, either maropitant citrate monohydrate or maropitant base, the same injection tolerance at the injection site was observed in terms of pain score. It is therefore concluded that the component influencing tolerance at the injection site is the antimicrobial preservative, and thus the selection and concentration of N-butanol is essential to the invention.

[0082] Study In a study, the local pain response after subcutaneous administration of a formulation known from the state of the art containing maropitant and metacresol as preservative (reference formulation) and the pharmaceutical composition according to the invention containing maropitant and N-butanol as preservative (test formulation) is compared.

[0083] The aim of this study was to compare the local pain response after subcutaneous injection of two maropitant formulations administered at refrigerated temperatures (approximately 4 °C) and at room temperature (approximately 25 °C) to healthy beagle dogs. The two maropitant formulations were the test and reference formulations. The test formulation was the antiemetic maropitant formulation of the invention with n-butanol as a preservative (Maropitant-BA), and the reference formulation was the antiemetic maropitant formulation with metacresol as a preservative (Maropitant-M).

[0084] The test formulation, which comprises the pharmaceutical composition according to the invention with maropitant and N-butanol, and the reference substance (maropitant formulation with metacresol) were administered to beagle dogs subcutaneously (sc).

[0085] Comparisons were made by measuring local pain after subcutaneous injection of the two formulations at refrigerated temperature (approximately 4 °C) and at room temperature (approximately 25 °C) in dogs.

[0086] Thirty-two healthy beagle dogs, 8 dogs per group, received four subcutaneous injections. Each dog received four subcutaneous administrations of 1 mg / kg maropitant, with a 7-day interval between treatments.

[0087] On study day DO, study animals in group 1 (dogs 1 to 8) were administered the test formulation (maropitant-BA) at 4°C, study animals in group 2 (dogs 9 to 16) were administered the reference formulation (maropitant-M) at 4°C, study animals in group 3 (dogs 17 to 24) were administered the test formulation (maropitant-BA) at 25°C, and study animals in group 4 (dogs 25 to 32) were administered the reference formulation (maropitant-M) at 25°C.

[0088] On study day D7, animals in group 1 (dogs 1 to 8) were administered the test formulation (maropitant-BA) at 25°C, and animals in group 2 (dogs 9 to 16) were administered the reference formulation (maropitant-M) at 25°C. Animals in group 3 (dogs 17 to 24) received the test formulation (maropitant-BA) at 4°C, and animals in group 4 (dogs 25 to 32) were administered the reference formulation (maropitant-M) at 4°C.

[0089] On study day D14, animals in group 1 (dogs 1 to 8) were administered the reference formulation (maropitant-M) at 4°C, animals in group 2 (dogs 9 to 16) were administered the test formulation (maropitant-BA) at 4°C, animals in group 3 (dogs 17 to 24) were administered the reference formulation (maropitant-M) at 25°C, and animals in group 4 (dogs 25 to 32) were administered the test formulation (maropitant-BA) at 25°C.

[0090] On study day D21, animals in group 1 (dogs 1 to 8) were administered the reference formulation (maropitant-M) at 25°C, animals in group 2 (dogs 9 to 16) were administered the test formulation (maropitant-BA) at 25°C, animals in group 3 (dogs 17 to 24) were administered the reference formulation (maropitant-M) at 4°C, and animals in group 4 (dogs 25 to 32) were administered the test formulation (maropitant-BA) at 4°C.

[0091] Body weight checks are carried out on day -1 (Dl) and before administration to the test animals on days D0, D7, D14 and D21.

[0092] Clinical examinations were performed before administration and 24 hours after each administration, and the injection sites were examined for local reactions.

[0093] Clinical examinations included measurement of rectal temperature and heart rate, general observations (loss of appetite, general appearance, physical condition, alertness, hydration status, capillary refill time (CRT), skin, eyes, ears, digestive system (vomiting, diarrhea, polydypsia), urinary system (polyuria), and circulatory system (epistaxis). The health status of all animals was good during the study period.

[0094] In all animals, local pain assessment was examined immediately after administration and within 2 minutes after administration. Pain was assessed and graded using two scales: Visual Analog Scale (VAS) scores were determined immediately after administration, and Simple Descriptive Scale (SDS) scores were determined 2 minutes after administration. In general, the animals' health was good throughout the study, and they showed good physical and normal behavioral status. The study was conducted without significant abnormalities. Dosing, local pain assessment, and all other activities related to this study were performed as described in the study protocol.

[0095] In summary, the statistical results show a trend towards higher values ​​for the reference formulation (MM) compared to the test formulation (M-BA) in arithmetic means (mean), standard deviations (SD), medians, minima, maxima and coefficients of variation of the SDS and VAS values ​​sorted by formulation, temperature within each formulation, administration period within each formulation and administration sequence within each formulation.

[0096] Statistically significant differences between the formulations were observed when comparing the two observers' geometric means for VAS ratings (p=0.003). No differences were observed between temperatures, administration times, or administration sequences.

[0097] Statistically significant differences were found between the formulations when comparing the two observers' medians for SDS values ​​(p=0.004). No differences were found between temperatures, time periods, or administration sequences.

[0098] Study design and methods

[0099] 2 / 3 mE syringes with 25G needles (0.50 x 16 mm) are used.

[0100] Animal groups

[0101] A total of 32 dogs (16 males and 16 females) are divided into four groups of eight animals each. Each dog is randomly assigned to one of the four groups. After randomization, the animals are numbered from 1 to 32.

[0102] Dosage information

[0103] The test and reference formulations are two different formulations of maropitant 10 mg / mU solution for injection. Each dog receives four subcutaneous administrations of 1 mg / kg maropitant in a volume of 0.1 mL / kg, with an interval of 7 days between treatments.

[0104] Each formulation is stored at refrigerated temperature (approx. 4°C) and at room temperature (approx.

[0105] 25°C). Approximately 1.5 to 2 hours before administration, one vial of the test and reference formulations is placed in an ice bath (approximately 4°C) and another vial of the test and reference formulation is placed in a preheated water bath (approximately 25°C).

[0106] The same dose was administered for all four administrations based on body weight measured on day -1.

[0107] The animal groups were distributed over the following administration days as shown in Table 4.

[0108] Table 4: Formulation, days of administration and temperature

[0109] A total of 32 dogs (8 per group) were randomly assigned by sex and body weight to each of the four homogeneous study groups. Method of administration

[0110] The test and reference formulations were administered to the beagle dogs subcutaneously (sc).

[0111] Subcutaneous Administration Procedure For subcutaneous administration, the animal was secured in a supine position on an examination table. After disinfecting the area with alcohol, the test and reference formulations were injected into the scapular region using a 2 / 3 mL syringe and a 25-gauge needle. Administration occurred between the scapulae (approximately 2.5 cm from the spine of the scapula). Two formulations each were administered at refrigerated temperature (approximately 4°C) and at room temperature (approximately 25°C). One needle remained in the temperature-controlled vial for product withdrawal. A new needle was used for each administration of the test and reference formulations.

[0112] The needle was inserted subcutaneously and after approximately two seconds the test or reference formulation was injected.

[0113] The sequence of injections was: cranial right, caudal right, caudal left and cranial left on days DO, D7, D14 and D21, respectively.

[0114] Immediately after administration, the animal was held individually during local pain assessment for 2 minutes after administration. The injection site was not massaged after administration.

[0115] Observations during use

[0116] Clinical examination

[0117] The animals receiving the formulations were observed throughout the trial period. Observations included a complete list of clinical signs and were performed immediately before administration (pre-dose) and 24 hours after administration in each test animal.

[0118] The following signs were assessed:

[0119] - General observations: general appearance, physical condition, alertness, hydration status

[0120] - Digestive system: vomiting, diarrhea

[0121] - Circulatory system: Epistaxis

[0122] No abnormal observations were made. Rectal temperature in all animals remained within the normal range of 37.5°C to 39.5°C throughout the study.

[0123] The individual heart rate values ​​of all animals were within the normal range throughout the study.

[0124] Investigation of the local reaction

[0125] The animals were examined throughout the experimental period. Observations were conducted at the following time points:

[0126] DO before administration and 24 hours (DI) after completion of subcutaneous administration. If a dog showed a local reaction on DI, daily assessments of the local reaction in that individual dog were continued until the signs disappeared.

[0127] The following signs were assessed:

[0128] - Local reaction: edema, swelling or nodules

[0129] - Pruritus (itching)

[0130] No abnormalities were observed in the test animals.

[0131] Assessment of local pain

[0132] The animals were examined throughout the experimental period. Observations were conducted at the following time points: D0, D7, D14, and D21, immediately after administration and for 2 minutes after administration.

[0133] Pain was assessed and graded using the following scales. The results of the visual analogue scale (VAS) were recorded immediately after administration, and those of the simple descriptive scale (SDS) were recorded within 2 minutes of administration.

[0134] Immediately after administration

[0135] Visual Analog Scale (VAS): A vertical line drawn across a 10-cm scale, with 0 representing no pain and 10 representing the worst possible pain. The 10-cm line was recorded on the corresponding control sheet.

[0136] During 2 minutes after administration Simple Descriptive Scale (SDS): here the score was determined from 0 (no pain) to 3 (severe reaction) (Table 5).

[0137] Table 5: Simple descriptive scale (SDS) Observer 1 and Observer 2 recorded the scores on two different forms, independently and at the same time.

[0138] The staff involved in the local pain assessment were allied to the treatment group.

[0139] The results of the assessment of local pain reactions using the visual analogue scale (VAS) and the simple descriptive scale (SDS) of observers 1 and 2, respectively, are contained in Tables 6 to 9 below.

[0140] Table 6: Results of the Visual Analogue Scale (VAS) in mm from Observer No. 1 on Day 0,

[0141] 7, 14 and 21 in all groups

[0142] Table 7: Results of the Visual Analogue Scale (VAS) in mm by Observer No. 2 on days 0, 7, 14 and 21 in all groups

[0143] Table 8: Results of the simple descriptive observation (SDS) in mm of observer no.

[0144] 1 on days 0, 7, 14 and 21 in all groups

[0145] Table 9: Results of the simple descriptive observation (SDS) in mm of observer no.

[0146] 2 on days 0, 7, 14 and 21 in all groups

[0147] Measurement of body weight

[0148] Body weight was measured before administration (pre-dose) at the following time points: D1, D0 before administration, D7 before administration, D14 before administration and D21 before administration.

[0149] Descriptive statistics

[0150] Arithmetic means, geometric means (mean), standard deviations, medians, minima, maxima, and coefficients of variation (CV%) were calculated for the visual analogue scale (VAS) values ​​immediately after administration. Descriptive statistics were calculated by product (reference, test) and temperature within each product (4° and 25°C), as well as by product (reference, test), temperature (4° and 25°C), and administration period (group).

[0151] Similarly, the means, medians, and ranges of the simple descriptive scale scores recorded during the 2 minutes after administration, sorted by the same variables as the VAS, were calculated. SPSS ver25 and Phoenix-WinNonlin were used.

[0152] Statistical comparisons

[0153] The comparison of the logarithmized values ​​of the VAS scores (geometric means of the two observer measurements) between the products and the temperatures was performed with a parametric statistical approach (analysis of variance) using the GLM procedure.

[0154] SDS comparisons (median of two observer measurements) were performed using a logistic regression model. In both cases, animal, product, temperature, time period, and sequence were used as fixed factors. If statistically significant differences were found, pairwise comparisons were performed using a two-tailed Student's t-test. Statistical significance was set at 0.05 in all cases. The SPSS version 25 program was used.

[0155] No concomitant treatments were administered during the study. No illnesses or disorders were observed in the animals.

[0156] The examples show possible embodiments, whereby it should be noted at this point that the invention is not limited to the specifically illustrated embodiments of the same, but rather various combinations of the individual embodiments with each other are also possible and this possibility of variation lies within the skill of the person skilled in the art in this technical field due to the teaching of technical action through objective invention.

[0157] The scope of protection is determined by the claims. However, the description and drawings must be used to interpret the claims. Individual features or combinations of features from the various embodiments shown and described may represent independent inventive solutions. The problem underlying these independent inventive solutions can be derived from the description.

[0158] All information on value ranges in this description is to be understood as including any and all sub-ranges thereof, e.g. the information 1 to 10 is to be understood as including all sub-ranges starting from the lower limit of 1 and the upper limit of 10, ie all sub-ranges begin with a lower limit of 1 or greater and end with an upper limit of 10 or less, e.g. 1 to 1.7, or 3.2 to 8.1, or 5.5 to 10.

[0159] For the sake of clarity, it should finally be pointed out that, in order to better understand the structure, some elements have been shown out of scale and / or enlarged and / or reduced in size.

Claims

Patent claims 1. A pharmaceutical composition comprising an aqueous solution containing 8 mg / mL to 12 mg / mL of maropitant or 12 mg / mL to 16 mg / mL of a pharmaceutically acceptable salt thereof, 55 mg / mL to 70 mg / mL of sulfobutyl ether-ß-cyclodextrin and 18 mg / mL to 30 mg / mL of n-butanol.

2. Pharmaceutical composition according to claim 1, characterized in that N-butanol is present in a concentration of 20 mg / mL to 25 mg / mL, in particular 21 mg / mL to 24 mg / mL, preferably 22 mg / mL.

3. Pharmaceutical composition according to claim 1 or 2, characterized in that the pharmaceutically acceptable salt of maropitant is maropitant citrate monohydrate and is present in a concentration of 13.5 mg / mL to 15.5 mg / mL, preferably 14.48 mg / mL.

4. Pharmaceutical composition according to one of claims 1 to 3, characterized in that sulfobutyl ether-ß-cyclodextrin is present in a concentration of 60 mg / mL to 65 mg / mL, preferably 63 mg / mL.

5. Pharmaceutical composition according to one of claims 1 to 4, characterized in that it has a pH of 3.0 to 6.

0.

6. Pharmaceutical composition according to one of claims 1 to 5, characterized in that it has a pH of 4.0 to 5.0, preferably of 4.3 to 4.

7.

7. Pharmaceutical composition according to one of claims 1 to 6, characterized in that the specific density of the pharmaceutical composition is between 1.01 g / cm 3 and 1.04 g / cm 3 , in particular 1.015 g / cm 3 and 1,030 g / cm 3 , preferably between 1.021 g / cm 3 and 1.025 g / cm 3 , lies.

8. Pharmaceutical composition according to any one of claims 1 to 7 for use as a medicament.

9. Pharmaceutical composition according to claim 8 for use in the treatment and prevention of nausea and vomiting in mammals, in particular dogs and cats.

10. A pharmaceutical composition for use according to claim 8 or 9, wherein the pharmaceutical composition is administerable parenterally by injection or infusion.

11. A pharmaceutical composition for use according to claim 10, wherein the pharmaceutical composition is administerable subcutaneously.

12. Multi-dose container comprising a pharmaceutical composition according to at least one of claims 1 to 11.

13. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 7, comprising the steps: (i) adding sulfobutyl ether-ß-cyclodextrin and maropitant, in particular maropitant citrate monohydrate, to water to obtain an aqueous solution, (ii) dissolving maropitant, in particular maropitant citrate monohydrate, in the aqueous solution, (iii) Addition of N-butanol to the solution and (iv) optionally adjusting the pH to a value between 3.5 and 5.5, in particular 4.0 to 5.0, preferably 4.3 to 4.7, by adding a pharmaceutically acceptable base or acid to the aqueous solution. A process for preparing a pharmaceutical composition according to claim 13, characterized in that sulfobutyl ether-ß-cyclodextrin is dissolved in water and then maropitant citrate monohydrate is added to the aqueous solution and mixed.

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