Production of sterile active pharmaceutical ingredients

Abstract

The invention refers to a process for preparing sterile active pharmaceutical ingredients (APIs) useful in the preparation of sterile product for ophthalmic use. The process comprises the gamma-ray sterilization treatment of the APIs powder in a protective atmosphere.

Claims

1. A process for preparation of a sterile Brinzolamide, the process comprising: placing a bulk powder of Brinzolamide inside a bag made of polyethylene; creating a protective atmosphere that replaces ambient air in the bag made of polyethylene; sealing the bag made of polyethylene; placing the sealed bag made of polyethylene inside a bag made of oxygen-and-humidity-proof high-barrier material, wherein the high barrier material is polylaminated aluminium or metallized foil coupled with polyester and polypropylene or polyethylene; creating a protective atmosphere that replaces ambient air in the bag made of oxygen-and-humidity-proof high-barrier material; wherein the protective atmosphere that replaces ambient air in the bag made of polyethylene and in the bag made of oxygen-and-humidity-proof high-barrier material is selected from vacuum, argon, nitrogen, and helium; sealing the bag made of oxygen-and-humidity-proof high-barrier material; and performing terminal gamma-ray sterilization treatment on the bulk powder of Brinzolamide.

2. The process according to claim 1, wherein the gamma-ray sterilization treatment is carried out with a radiation of 25 kGy.

3. The process according to claim 1, wherein the gamma-ray sterilization treatment is carried out on the Brinzolamide powder packed under vacuum.

4. The process according to claim 1, wherein the gamma-ray sterilization treatment is carried out on the Brinzolamide powder packed in nitrogen or helium atmosphere.

5. The process according to claim 1, wherein the gamma-ray sterilization treatment is carried out at room temperature or below zero up to 78 C.

6. The process according to claim 2, wherein the gamma-ray, sterilization treatment is carried out at 78 C., with a radiation of 25 kGy and on the Brinzolamide powder packed in helium atmosphere.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The present invention makes it possible to meet the above mentioned requirements thanks to the use of gamma rays for the sterilisation of Brinzolamide, carrying out the process after the micronisation process.

(2) The term protective atmosphere refers to any atmosphere that replaces ambient air. suitable protective atmospheres include vacuum, argon, nitrogen, or helium, preferably vacuum, nitrogen or helium atmosphere

(3) According to the present process, the sterilisation procedure may be carried out on the powder product packed under vacuum in a suitable container, such as a sealed bag made of a suitable plastic material, preferably polyethylene; this container is in its turn sealed in another bag made of oxygen and humidity proof, high barrier materials such us polylaminated aluminium or metallized foil coupled with plastic material such as polyester and polypropylene or polyethylene, to avoid the presence of oxygen and humidity during irradiation and to isolate the sterile material from the external environment in order to keep the initial sterility level.

(4) We found surprising the role of oxygen in the degradation process during sterilization process, since the gamma-ray could promote the activation of molecular oxygen in radical species (singlet-triplet shift) that decompose the brinzolamide molecule. The role of the oxygen is more evident in the micronized powder since the surface area is going to increase dramatically with the decrease of the size of the particles; with the increasing of the surface area there is the increase of the surface exposed to air so the behaviour of the micronised powder is completely different from the behaviour of the non micronised powder and based on the state of the art this was unpredictable. In a preferred embodiment of this invention the protective packaging is performed in modified atmosphere (nitrogen or helium) in order to completely remove oxygen, then material is vacuum sealed. The packaging material has the crucial role to isolate the drug substance from the external environment, so during sterilization process avoid contact with oxygen and after the sterilization process maintain the sterility grade.

(5) The sterilisation step according to the process of the invention was validated according to EU GMP and European Medicines Agency guidelines: Use of Ionising Radiation in the manufacture of Medicinal Products Annex 12 and 3AQ4a, taking also in consideration ISO guideline UNI EN ISO 11137-1-2-3: 2006. The validation work guarantee a Sterility Assurance Level (SAL) of at least 10.sup.6 and the so obtained product is sterile according to the criteria of European Pharmacopoeia and US Pharmacopoeia. Gamma ray are produced from Cobalt 60 source, the process applies to micronised or not micronised powder packed in high barrier materials, Brinzolamide is a dry powder complying with the current USP monograph, the terms micronised powder is related to a fine powder with 90% of particle size distribution below 20 micron or less. The drug substance has a low bioburden, typically less than 10.sup.3 CFU per gram for which the prescribed dose of 25 KGy is suitable to have the required SAL less than 10.sup.6. The sterilisation process could be performed at ambient temperature or below zero up to 78 C.

(6) It was proved by the Applicant that the present sterilisation procedure, when applied to Brinzolamide in bulk powder form, does not cause significant degradation process or when an increase is observed, it is lower than the prescribed specification of USP test for related substances: not more than 0.3% of single impurity and 1.0% of total sum of impurities; and more in general the resulting sterile product is fully in compliance with all the quality criteria established by US Pharmacopoeia relevant monograph. The sterile active pharmaceutical ingredient (APIs), preferably Brinzolamide, obtained according to the process of the invention are used together with pharmaceutically acceptable carrier for preparing pharmaceutical composition.

(7) The sterile Brinzolamide obtained according to the process of the invention is used together with pharmaceutically acceptable carrier for preparing pharmaceutical composition for the treatment of open-angle glaucoma and raised intraocular pressure.

EXAMPLES

(8) The following examples will further illustrate the present invention without, however limiting it thereto.

(9) All the analysis were performed according to USP Brinzolamide monograph, sterility and bioburden test were performed according to Eur. Ph. and USP.

(10) Two related substances (impurities) are described in the USP monograph: Impurity A and Impurity B.

(11) Impurity A is the enantiomer of Brinzolamide, typically produced upon heating of the drug substance solutions, that is the main degradation product of the process described in the EP 941094 B1, since the sterilization process is performed in autoclave at 120 C.

(12) ##STR00001##

(13) Impurity A. (S)-4-(Ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide

(14) Impurity B is the des-ethyl analogue of Brinzolamide, typically produced upon UV light stress or under radiation exposure, like gamma ray sterilization process.

(15) ##STR00002##

(16) Impurity B. (R)-4-amino-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide

(17) Other impurities (Impurity C and Impurity D) were commonly found in Brinzolamide drug substances arising from the manufacturing process and/or from the gamma-ray sterilization treatment.

(18) ##STR00003##

(19) Impurity C. 4-hydroxy-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide

(20) ##STR00004##

(21) Impurity D. 4-oxo-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide

(22) Additional detectable impurities were found typically as degradation byproducts of the gamma ray treatment, they are not considered individually but only as sum of impurities (both known and unknown):

(23) ##STR00005##

(24) 3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1 dioxide

(25) ##STR00006##

(26) (R)-4-(Ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonic acid 1,1-dioxide

Example 1

(27) Four Different samples of Brinzolamide USP grade (3 g each not-micronized material), were packed in LDPE liner inside a Barrier Composite Foil (Polyester, Aluminium, HDPE), each package was exposed to different radiation grade: 10, 15, 20 and 25 KGy at room temperature (RT). The material was tested according to USP, details about appearance of the powder, related substances and sterility were given in Table 1.

(28) TABLE-US-00001 TABLE 1 Test 10 KGy, RT 15 KGy, RT 20 KGy, RT 25 KGy, RT Appearance White powder White powder Greenish powder Greenish powder Impurity A Not detected Not detected Not detected Not detected Impurity B 0.06% 0.07% 0.10% 0.10% Impurity C: <0.05% <0.05% <0.05% <0.05% Impurity D: 0.11% 0.14% 0.19% 0.21% Total Impurities 0.2% 0.2% 0.3% 0.4% Sterility Sterile Sterile Sterile Sterile

(29) All the samples complies with the USP specifications apart the appearance of the powder in the 20 and 25 KGy trials.

Example 2

(30) One sample of micronised Brinzolamide (100 g) USP grade was packed in LDPE liner inside a double Barrier Composite Foil (Polyester, Aluminium, HDPE), the material was exposed to a radiation of 25 KGy at room temperature. The material was tested according to USP, details about appearance of the powder, related substances and sterility were given in Table 2.

(31) TABLE-US-00002 TABLE 2 Test 25 KGy, RT Appearance Almost White powder Impurity A Not detected Impurity B 0.29% Impurity C <0.05% Impurity D 0.62% Total Impurities 1.4% Sterility Sterile

(32) The sample does not complies with USP specification

Example 3

(33) One sample of micronised Brinzolamide (100 g) USP grade was packed under vacuum in LDPE liner inside a double Barrier Composite Foil (Polyester, Aluminium, HDPE), the material was exposed to a radiation of 25 KGy at room temperature. The material was tested according to USP, details about appearance of the powder, related substances and sterility were given in Table 3.

(34) TABLE-US-00003 TABLE 3 Test 25 KGy, RT, under vacuum Appearance White powder Impurity A Not detected Impurity B 0.09% Impurity C <0.05% Impurity D 0.30% Total Impurities 0.6% Sterility Sterile

(35) The sample complies with USP specification

Example 4

(36) One sample of micronised Brinzolamide (100 g) USP grade was packed under vacuum and under controlled atmosphere (nitrogen) in LDPE liner inside a double Barrier Composite Foil (Polyester, Aluminium, HDPE), the material was exposed to a radiation of 25 KGy packed in dry ice at 78 C. The material was tested according to USP, details about appearance of the powder, related substances and sterility were given in Table 4.

(37) TABLE-US-00004 TABLE 4 Test 25 KGy, 78 C., N.sub.2, under vacuum Appearance White powder Impurity A Not detected Impurity B 0.08% Impurity C <0.05% Impurity D 0.16% Total Impurities 0.3% Sterility Sterile

(38) The sample complies with USP specification

Example 5

(39) One sample of micronised Brinzolamide (100 g) USP grade was packed under vacuum and under controlled atmosphere (helium) in LDPE liner inside a double Barrier Composite Foil (Polyester, Aluminium, HDPE), the material was exposed to a radiation of 25 KGy packed in dry ice at 78 C. The material was tested according to USP, details about appearance of the powder, related substances and sterility were given in Table 5.

(40) TABLE-US-00005 TABLE 5 Test 25 KGy, 78 C., He.sub.2, Appearance White powder Impurity A Not detected Impurity B 0.06% Impurity C <0.05% Impurity D 0.11% Total Impurities 0.2% Sterility Sterile

(41) The sample complies with USP specification