Stable multiple dose cyclosporin water-in-oil emulsion compositions

Abstract

The present invention relates to the field of pharmaceutical technology and relates to emulsion compositions comprising the active pharmaceutical ingredient Cyclosporin and the method of preparing this composition.

Description

[0001] STABLE MULTIPLE DOSE CYCLOSPORIN WATER-IN-OIL EMULSION

[0002] COMPOSITIONS

[0003] Technical Field

[0004] The present invention relates to the field of pharmaceutical technology and concerns an emulsion composition containing the active pharmaceutical ingredient Cyclosporin and the method of preparing this composition.

[0005] Prior Art

[0006] Cyclosporin is a topical ophthalmic anti-inflammatory drug. It is used to treat severe keratitis, which is inflammation of the cornea (the transparent layer covering the front of the eye), in adult patients with dry eye disease when treatment with artificial tears (tear substitutes) is insufficient to improve the condition.

[0007] The chemical name of Cyclosporin, which has a molecular weight of 1202.6 g / mol, is 1,11-

[0008] Anhydro[L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-

[0009] (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-(methylamino)oct-6-enoyl-(2S)-2-aminobutanoyl-N- methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucine], and it has the structure shown in Figure 1 below.

[0010] Figure 1. Cyclosporin is marketed in the UK by Santen UK Limited under the brand names Ikervis and Verkazia® as an eye drop emulsion at a dosage of 1MG / ML. The formulations (including excipients) of these two products are identical, with the only difference being their indications. Ikervis is used for the treatment of severe keratitis in adult patients with dry eye disease, which persists despite treatment with tear substitutes. Verkazia is indicated for the treatment of severe vernal keratoconjunctivitis (VKC) in children aged 4 years and older and adolescents.

[0011] Cyclosporin A is a white or off-white odorless powder that is insoluble in water and n-hexane but soluble in methanol, ethanol, acetone, and chloroform.

[0012] In the state of the art, various patents related to Cyclosporin exists.

[0013] EP2049079 Bl patent belong to SANTEN SAS covers a oil-in-water emulsion composition comprising an oily phase, 0.001 to 0.02% by weight of C16-alkyl quaternary ammonium halogen, a surfactant, and water.

[0014] EP2404593 Bl patent belong to SANTEN SAS covers a oil-in-water emulsion composition containing 1-5% by weight of an oily phase (selected from medium-chain triglycerides or mineral oils) and 0.0005 to 0.1% by weight of Cetrimonium Chloride.

[0015] EP1891939 Bl patent belong to SANTEN SAS covers an emulsion composition containing at least 20% by weight of a quaternary ammonium halogen with at least 14 carbons and at least 5% by weight of a quaternary ammonium halogen with at least 16 carbons.

[0016] EP1809237 Bl patent belong to Novagali relates to an ophthalmic emulsion composition.

[0017] EP1991249 Bl patent belong to ALLERGAN, INC. covers ophthalmic administration to the eye for the treatment of vision loss due to corneal thinning.

[0018] EP2621469 Bl patent belong to NEUROVIVE relates to an emulsion containing 5g / L of Cyclosporin.

[0019] EP2779994 Bl patent belong to ALLERGAN INC. relates to a formulation containing Cyclosporin A in crystal form 2. EP2827840 Bl patent belong to LABORATOIRES THEA covers an aqueous ophthalmic formulation containing Cyclosporin A, a cellulose derivative, a polyvinyl derivative, and macrogolglycerol hydroxystearate.

[0020] EP3399962 Bl patent belong to NOVALIQ relates to a formulation containing 0.05% - 0.1% Cyclosporin and 1 -perfluorobutylpentane, used for the treatment of dry eye symptoms with twice-daily administration.

[0021] Brief Description of the Invention

[0022] The present invention, as expressed in more detail in the following examples and claims, describes a composition in which the exact amount of the active pharmaceutical ingredient Cyclosporin can be precisely obtained through an appropriate manufacturing method. The invention also details the preparation of the composition in a multiple-dose form rather than a single-use form, thereby reducing manufacturing costs and making it easier for the patient to use.

[0023] Detailed Description of the Invention

[0024] The present invention relates to an emulsion composition comprising the active ingredient Cyclosporin.

[0025] The present invention relates to a pharmaceutical emulsion composition comprising 1 mg of Cyclosporin per 1 ml (0.1%) as the active ingredient.

[0026] The composition comprises at least one or an appropriate mixture of surfactants, solvents, and pH-adjusting agents.

[0027] In the composition of the invention, oils such as castor oil, medium-chain triglycerides, and vegetable oils may be used as the oil phase. In the emulsion composition of the invention, a medium-chain triglyceride, which is an oily solvent, has been used as the oil phase.

[0028] In the composition of the invention, water and glycerol have been used as solvents, tyloxapol and poloxamer as surfactants, cetalkonium chloride as a cationic surfactant, and sodium hydroxide as a pH-adjusting agent. Emulsion formulations can be prepared as water in oil or oil in water, depending on their phases. If the emulsion contains oil droplets in water, it is called an O / W (oil in water) emulsion, and if it contains water droplets in oil, it is called a W / O (water in oil) emulsion. W / O type emulsions can be prepared by adding water to oil, and O / W emulsions can be prepared by adding oil to the water phase.

[0029] In the composition of the present invention, it has been determined that the W / O form, that is, the addition of water to the oil phase, provides better quantitative results compared to the O / W form, which involves adding oil to the water phase.

[0030] Cyclosporin active ingredient is insoluble in water and thus dissolves in the oil phase. During the addition of the oil phase to the water phase, problems arise in the complete addition of the oil phase, leading to losses of the active ingredient. This problem results in a lower amount of the active ingredient being present.

[0031] In the present invention, this problem is solved by preparing the emulsion in the W / O form, that is, by adding the water phase to the oil phase.

[0032] Furthermore, upon reviewing previous searches and products on the market, it is observed that emulsions comprising 0.1% Cyclosporin have always been prepared in single-dose vials. These single-dose vials contain 0.4 mL of emulsion and are used by applying one drop to each eye. Consequently, once the vial is opened, the remaining product cannot be reused and must be discarded immediately.

[0033] In the present invention, a formulation and manufacturing method were developed to create a multiple-dose form by using a special bottle-cap system instead of a single-dose vial.

[0034] The multi-dose emulsion’s bottle-cap system, Novelia®, is a multi-dose closing tip system that eliminates the need for preservatives in the drug and prevents bacterial contamination throughout the treatment period. Novelia® is an innovative ophthalmic multi -dose dropper with a valve system and Pure Flow technology that filters the air returning to the bottle, preventing contamination of the contents. Novelia® features a one-way valve that ensures contaminated fluid does not return to the bottle after a drop is dispensed, completely eliminating the need for filtering the fluid.

[0035] Air enters the dropper through a separate ventilation system with a silicone membrane, known as PureFlow® technology. This provides a continuous homogeneous material barrier that guarantees the integrity of the system.

[0036] In the present invention, the emulsion prepared in a multi-dose form facilitates patient use and prevents product wastage.

[0037] The composition of the invention is applied ophthalmically. The following examples relate to the composition of the invention and are not in any way limiting to the scope of the invention.

[0038] Examples

[0039] Example 1. (Comparative Basis O / W Composition Example)

[0040] Example 1 Table la shows the composition of the O / W emulsion used in the comparison.

[0041] Prepared according to the process briefly described below:

[0042] 1. Medium-chain triglyceride, Tyloxapol, Glycerol, Cetalkonium chloride, and Pol oxamer 188 are weighed and mixed, bringing the temperature to the range of 50°C-60°C. Cyclosporin is weighed and added, then mixed.

[0043] 2. Water is brought to the temperature range of 50°C-60°C. 3. The mixture from step 1 is added to the water phase from step 2 while stirring and running the homogenizer at high speed, and the mixing process is continued. The mixture is then filtered.

[0044] 4. The temperature is brought to the range of 20°C-25°C, pH adjustment is made, and the volume is completed.

[0045] The amount determination analysis of the O / W emulsion composition prepared by the above process (formulation in Table la) has been carried out. The analysis results are given in Table lb.

[0046] Table lb.

[0047] Example 2

[0048] Example 2 related to the composition of the W / O emulsion of the invention is shown in Table 2a.

[0049] Prepared according to the process briefly described below:

[0050] 1. Medium-chain triglyceride, Tyloxapol, Glycerol, Cetalkonium chloride, and Pol oxamer 188 are weighed and mixed, bringing the temperature to the range of 50°C-60°C. Cyclosporin is weighed and added, then mixed.

[0051] 2. Water is brought to the temperature range of 50°C-60°C and is gradually added to the above mixture until phase formation is observed. At the point where phase formation is observed, the addition of the water phase is stopped, and the mixing process is continued with stirring and high-speed homogenization. The mixture is then filtered. 3. After the two phases are completely mixed, most of the water at the same temperature is added.

[0052] 4. The temperature is brought to the range of 20°C-25°C, pH adjustment is made, and the volume is completed.

[0053] The amount determination analysis of the W / O emulsion prepared with the present invention (formulation in Table 2a) has been carried out. The analysis results are given in Table 2b. Table 2b.

[0054] The zeta potential values, which are indicators of the stability of the emulsions, for the composition in Table 2a and the formulations in Table 2b have also been checked and are presented in Table 3.

[0055] Table 3.

[0056] When the two examples above, along with the amount determination results and zeta potential results, are examined, it is observed that preparing the emulsion manufacturing method as W / O, i.e., by adding the water phase to the oil phase, yields good results in all aspects.

[0057] As seen in the results of Example 2, the present invention achieves a multi-dose emulsion product with the desired appropriate amount determination.

Claims

CLAIMS1. An emulsion composition comprising Cyclosporin, characterized by the composition comprising 1 mg of Cyclosporin per 1 ml (0.1%) and the emulsion is in the form of water-in-oil (W / O).

2. The emulsion composition in the form of water-in-oil (W / O) according to claim 1, characterized by the composition comprising Cetalkonium Chloride as a cationic surfactant.

3. The emulsion composition in the form of water-in-oil (W / O) according to any of the preceding claims, characterized by the composition comprising Tyloxapol and / or Poloxamer as surfactants.

4. The emulsion composition in the form of water-in-oil (W / O) according to any of the preceding claims, characterized by the composition comprising Glycerol and / or Water as solvents.

5. The emulsion composition in the form of water-in-oil (W / O) according to any of the preceding claims, characterized by the composition comprising Sodium Hydroxide as a pH-adjusting agent.

6. The emulsion composition in the form of water-in-oil (W / O) according to any of the preceding claims, characterized by the composition comprising Medium-chain triglycerides as an oily solvent.

7. The emulsion composition in the form of water-in-oil (W / O) according to any of the preceding claims, characterized by the Cyclosporin amount determination in the composition is greater than 95%.

8. The emulsion composition in the form of water-in-oil (W / O) according to any of the preceding claims, characterized by the composition having a zeta potential value greater than +10 mV.

9. The emulsion composition in the form of water-in-oil (W / O) according to any of the preceding claims, characterized by the composition is applied ophthalmically.

10. The emulsion composition in the form of water-in-oil (W / O) according to any of the preceding claims, characterized by the composition is applicable in multiple doses.

11. The emulsion composition in the form of water-in-oil (W / O) according to any of the preceding claims, characterized by the composition is packaged with a Low-Density Polyethylene (LDPE) bottle and a High-Density Polyethylene (HDPE) cap.

12. A process for preparing an emulsion composition in the form of water-in-oil (W / O) according to any of the preceding claims, characterized by the addition of the water phase into the oil phase during the process.

13. The process according to claim 12, characterized by the addition of the water phase into the oil phase while the homogenizer is operating at high speed.

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