The present invention relates to a method of sterilization of corticosteroids, wherein the process is carried out in nylon bags with use of indicators. The invention more particularly relates to dry heat sterilization of loteprednol etabonate. The invention further relates to formation of various pharmaceutical dosage forms using sterile corticosteroid and their use to treat allergic and/or inflammatory conditions.

BACKGROUND OF THE INVENTION

As the non-sterile preparations may subject the patient to an unnecessary risk of secondary infection from the contaminating microbe, therefore sterility of pharmaceutical preparations plays important role. There are various methods which are used for sterilization. However, the problem associated with many sterilization procedures is that the process often results in unfavourable changes in the drug product. These changes can range from loss of activity, to increased degradation or possible alteration of the chemical or physical characteristics. These problems are especially pronounced when corticosteroids are sterilized. Chemical sterilization has been based on exposure to toxic compounds, e.g. ethylene oxide. Further, it has been found to leave residual amounts of ethylene oxide in the drug preparation. Irradiation based sterilization is known for corticosteroids, however significant degradation has been reported with that process.
US 8791096 B2 relates to moist heat sterilization of glucocorticosteroid like budesonide and beclomethasone.
US 2006/140816 A1 relates to a process for the steam sterilization of beclomethasone comprising heating a mixture of micronized beclomethasone and water at a temperature ranging between 100 and 130°C for a time sufficient to sterilize the mixture.
US 6392036 B1 relates to process for sterilization of glucocorticosteroid like budesonide, prednisolone, beclomethasone by using dry heat sterilization with temperature of 100°C to 130 °C.
US 9649319 B2 discloses a method for preparing a sterile ophthalmic suspension comprising Loteprednol etabonate and sterilization of Loteprednol etabonate by Dry Heat Sterilization which is done at a temperature below 200° C. for 1-10 hours.
None of the prior art discloses use of nylon bags along with indicator to carry sterilization of corticosteroids.
Accordingly, there is a need for developing such a method for sterilization of corticosteroids which can ensure that sterilization process has been carried out efficiently without any degradation. The present inventors have found that sterilizing the corticosteroid in nylon bag using indicators lead to desired results.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, there is provided a method of sterilization of corticosteroid which comprises the steps of placing the corticosteroid in a nylon bag, and performing dry heat sterilization using indicator.
According to one embodiment of the present invention, the corticosteroid is loteprednol or loteprednol etabonate.
According to another embodiment of the present invention, the indicator is selected from physical indicator, chemical indicator and/or biological indicator.

DESCRIPTION OF THE PRESENT INVENTION

The present invention provides a method of sterilization of corticosteroid using nylon bags and indicators.
The corticosteroids used in the invention includes, loteprednol, dexamethasone, beclomethasone, betamethasone, prednisolone, methylprednisolone or their salts or esters thereof. Most preferably, loteprednol etabonate.
Loteprednol etabonate is chemically known as Chloromethyl 17a-[(ethoxycarbonyl)oxy]-11ß-hydroxy-3-oxoandrosta-1,4-diene-17ß-carboxylate and disclosed in US 4996335. Loteprednol is indicated for the treatment of steroid responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe such as allergic conjunctivitis, acne rosacea, superficial punctuate keratitis, herpes zoster keratitis, iritis, cyclitis, selected infective conjunctivitis, when the inherent hazard of steroid use is accepted to obtain an advisable diminution in edema and inflammation. It is also indicated for the treatment of post-operative inflammation following ocular surgery.
The sterilization indicators can be a chemical indicator or biological indicator or any other indicator.
Chemical Indicator:
Dry Heat Chemical Process Indicators (CPIs) have been validated as per standard cycles outlined in ISO and USP for Depyrogenation processes. It provides a fast and consistent visual check on items there were exposed to Dry Heat processes as represented in Fig. 1.
Biological indicator:
The biological indicator consists of a 7 mm x 38 mm filter paper strip inoculated with Bacillus atrophaeus spores, packaged in a white glassine pouch. The configuration offers an increased D value at 160°C of not less than 2.5 minutes meeting the requirements for dry heat resistance as outlined in ISO 11138-4.
Biological indicators are test systems that contain viable microorganisms with a defined resistance to a specific sterilization process. They help monitor whether the necessary conditions were met to kill a specified number of microorganisms for a given sterilization process. For this reason, biological indicators are one of the most critical components of the sterilization process.
Biological indicators are generally considered the highest standard for monitoring the sterilization process. Biological indicators use bacterial spores that are enclosed in a smaller container that is placed inside the sterilizer. After going through the sterilization process the biological indicators are incubated to determine if any bacterial spores survived. If all bacterial spores are eliminated the indicator shows the sterilization process was effective and the medical items in the sterilizer should have zero or significantly fewer microorganisms on them.
A chemical indicator on a package verifies exposure to a sterilisation process. This helps differentiate sterilised from unsterilised items. More importantly, it helps monitor physical conditions within the steriliser to alert personnel if the process has been inadequate. A chemical indicator can detect steriliser malfunction or human error in packaging or loading the steriliser.
Nylon bags/pouches can be notched on edges for easy opening. They are clear, strong and puncture resistant.
The sterilization method as per the present invention involves heating the corticosteroid at a temperature of from 140°C-180°C.
In order to conduct the effective sterilization as per the present invention, the time required is from about 2 minutes to about 120 minutes.
To be sterile means that a product or composition meets the criteria of sterility according to the US Pharmacopoeia, or its counterpart in other jurisdictions, and which provides a therapeutically acceptable corticosteroid and/or pharmaceutical formulation.
The sterile corticosteroid prepared according to the invention are optionally formulated in a pharmaceutically acceptable vehicle with any of the well-known pharmaceutically acceptable excipients to prepare gel, eye drops, suspension, solution, emulsion, injection or any other suitable dosage form thereof. The type of pharmaceutically acceptable excipient employed will vary depending upon mode of administration and desired dosage form.
The invention also provides for use of sterile corticosteroid compositions for use in the treatment of various allergic and/or inflammatory conditions. The allergic and/or inflammatory conditions include, without limitation, eye diseases, contact dermatitis, conjunctivitis, acne rosacea, keratitis.
The following examples are intended to further illustrate certain embodiments of the invention and are not limiting in nature.

EXAMPLE 1
DRY HEAT STERILIZATION OF LOTEPREDNOL ETABONATE
i. Take an empty new nylon bag with indicator containing adhesive gum on opening edge of nylon bag
ii. Dispense required quantity of non-sterile material in nylon bag for dry heat sterilization and close with adhesive gum
iii. Further nylon bag containing loterprednol etabonate is packed in another nylon bag
iv. Charge the sealed nylon bag in Dry Heat Sterilizer
v. Start the DHS cycle as per validated parameter of DHS
vi. After completion of DHS cycle, remove the nylon bag from DHS and ensure for change in the color of indicator
vii. Use the material for sterile processing
The procedure of step 1 was used to sterilize loteprednol. The results as represented in Fig. 2 clearly reflects that sterilization method was effective as indicated by change of colour of indicator.

Claims:We Claim:
1. A sterilization method comprising the steps of:
(i) placing the corticosteroid in a nylon bag, and
(ii) performing dry heat sterilization of nylon bag containing corticosteroid using indicator.

2. The sterilization method according to claim 1, wherein the corticosteroid is loteprednol or loteprednol etabonate.

3. The sterilization method according to claim 1, wherein the indicator is selected from physical indicator, chemical indicator and/or biological indicator.

4. The sterilization method according to claim 1, wherein the heating is at a temperature of from 140°C-180°C.

5. The sterilization method according to claim 1, wherein the heating is carried out for 2 to 120 minutes.