DESC:FIELD OF THE INVENTION

The present invention relates to liquid dispensing container impregnated with antimicrobial material to prevent the spread of microbial contaminants in the therapeutically active composition(s) or cosmetic(s), wherein said antimicrobial material is evenly distributed throughout the container.

BACKGROUND OF THE INVENTION

Repeatedly used compositions, especially for cosmetics or pharmaceutical products, are exposed to ambient air and/or the application means. Containers and/or delivery devices for such compositions may be susceptible to contamination. Medications in particular sterile liquid medications for ophthalmic, parenteral, otic, or nasal administration, but also other liquid or pasty substances such as cosmetics, gets contaminated after opening container for use by invading microbes and eventually become unusable. In common such contamination is prevented by the including preservatives in the composition. However, use of preservatives in the formulation meant to be injected or directly instilled into body cavity such as eye lead to undesirable side effects, particularly from long-term use, ranging from temporary irritation and discomfort to even more complex issues in glaucoma.

Maintaining the sterility of such products is important for patient health and is a stringent regulatory requirement. Other alternatives known in prior art are single use containers which are expensive. Some containers are coated with antimicrobial agents only at certain surfaces such as nozzle tip. Hence, such containers become useless after first few uses and need to be discarded, making the technology expensive to use.

Based on the drawbacks of the prior arts, the present invention is focussed on providing liquid dispensing containers impregnated with antimicrobial material to prevent the spread of microbial contaminants in the therapeutically active composition(s) or cosmetic(s), wherein said antimicrobial material is evenly distributed throughout the container. Also, other issues such as compatibility and stability of the composition is not compromised. The present invention also provides a process for preparing such containers.
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SUMMARY OF THE INVENTION

The present invention relates to a liquid dispensing container impregnated with an antimicrobial material to prevent the spread of microbial contaminants in the therapeutically active composition(s) or cosmetic(s), wherein said antimicrobial material is evenly distributed throughout the container.

In one aspect of the present invention, the liquid dispensing container is made from a polymeric material embedded or coated with an antimicrobial agent.

Another aspect of the present invention provides a liquid dispensing container for dispensing sterile formulations having no preservatives.

Another aspect of the present invention provides a method for dispensing a preservative free therapeutically active formulation(s) or cosmetic product(s), wherein said method involves storing the therapeutically active formulation(s) or cosmetic product(s) in a container made up of a polymeric material having antimicrobial efficacy throughout the polymeric material and wherein said antimicrobial efficacy is achieved by embedding or coating the antimicrobial agent into or onto the polymeric material.

Another aspect of the present invention provides a liquid dispensing container made of a polymeric material impregnated with an antimicrobial agent, wherein said antimicrobial agent includes beads comprising silver phosphate glass powder having not more than 3.0% of silver, preferably not more than 2.5% of silver and most preferably, not more than 1.5% of silver.

Another aspect of the present invention provides a liquid dispensing container made of a polymeric material impregnated with an antimicrobial agent, wherein said antimicrobial agent includes beads comprising silver phosphate glass powder and the container comprises silver in an amount in the range between = 20 µg/g to = 110 µg/g.

DESCRIPTION OF THE INVENTION

The present invention relates to a liquid dispensing container made of a material impregnated with an antimicrobial material to prevent the spread of microbial contaminants in a therapeutically active composition(s) or cosmetic(s).

The “liquid dispensing container” can be syringes, bottles for any sterile product such as otic products, sterile nasal products, ophthalmic products, parenteral, tubes or bottles for pharmaceutical or cosmetic products, bottles for pharmaceutical vehicles and the like. The liquid dispensing container can be a glass container, a plastic container, or made up of any metallic or non-metallic material suitable for pharmaceutical, cosmetic, and medicinal purposes. The antimicrobial agent can be embedded within and/or adsorbed on the surface of any material that can be formed into any type of a dispensing container for pharmaceutical, cosmetic, and medicinal purposes. In particular, the liquid dispensing container(s) of the present invention are configured to store preservative free therapeutically active formulation(s) or cosmetic product(s).

The “therapeutically active composition(s) or cosmetic(s)” is a liquid or a semisolid dosage form selected from solution, emulsion, suspension, gel, gel forming suspension, and the like. In particular, sterile compositions such as compositions for ophthalmic, parenteral, otic, or nasal administration.

The “antimicrobial agent” means a substance that kills, delays the growth of, or prevents the growth of one or more microorganisms. Antibacterial is selected from the group comprising silver, triclosan, zinc, zinc, copper, cerium, or their ionic forms alone or in any combination thereof, preferably silver or its ionic form.

The present invention provides liquid dispensing container made of a polymeric material comprising a polymer and an antimicrobial dispersed and evenly distributed throughout the polymer.

The “polymer material” is made of one or more polymers selected from the group comprising low density polyethylene, high density polyethylene, high impact polystyrene, polypropylene, polystyrene, polyethylene terephthalate, polyvinyl chloride, polycarbonate, and the like or combinations thereof.

According to one embodiment, the present invention provides the liquid dispensing container made from a polymeric material embedded or coated with an antimicrobial throughout the container.

The present invention further provides a liquid dispensing container made of a polymeric material comprising a matrix of polymer and an antimicrobial embedded throughout the polymer, wherein the antimicrobial agent is present in form of powder or beads.

According to one embodiment of the present invention, the beads comprising antimicrobial agent are a matrix system or a reservoir system optionally with one or more additional components or inert excipients.

According to another embodiment of the present invention, the antimicrobial agent can be adsorbed onto the surface of the polymeric material of the container, i.e., polymeric material can be coated with the antimicrobial agent. In other words, the surface of the polymeric material can be treated with the antimicrobial agent.

According to another embodiment of the present invention, the antimicrobial agent comprises silver phosphate glass powder sintered under a nitrogen atmosphere or sintered under an oxygen atmosphere to form beads.

In another embodiment of the present invention, the antimicrobial agent includes beads made up of silver phosphate glass powder having not more than 3.0% of silver concentration, preferably not more than 2.5% of silver concentration and most preferably, not more than 1.5% of silver concentration.

In another embodiment, the silver phosphate glass powder contains silver ions that are entrapped inside a glass matrix. Whenever the surface of the container comes in contact of the microbes, these silver ions migrate to the surface of the polymer material of the container and penetrate the microbe cell thereby puncturing the cell membrane and killing it. The silver ions get released only to neutralize the negatively charged microbes.

The silver phosphate glass powder contains about 5.0% of silver, preferably about 2.5% of silver, more preferably about 1.5% of silver.

According to one embodiment of the present invention, the liquid dispensing container comprises silver in an amount in the range between = 20 µg/g to = 110 µg/g.

According to one embodiment, the silver phosphate glass powder has a particle size, i.e., d50 less than 50 microns, preferably, less than 25 microns.

According to one embodiment, the beads of silver phosphate glass powder has a particle size, i.e., d50 of less than 200 microns, preferably, less than 100 microns, more preferably, less than 50 microns.

In another embodiment, the therapeutically active composition is solution, emulsion, suspension, gel, lotion, or gel forming suspension dosage form, and the therapeutically active agent is selected from the group consisting of anti-inflammatory, analgesics, anti-infective(s), corticosteroid(s), muscarinic receptor agonist(s) and antagonist(s), alpha receptor agonist(s) and antagonist(s), beta receptor agonist(s) and antagonist(s) such as bimatoprost, brimonidine, timolol, brinzolamide, bromofenac, dexpanthenol, gatifloxacin, olopatadine, cyclosporine, gatifloxacin, ocufloxacin, moxifloxacin, phenylephrine, pilocarpine, budesonide, triamcinolone, polymixin, prednisolone, difluprednate, dorzolamide, ciprofloxacin, diclofenac, carnitine, ketorolac, loteprednol, dexamethasone, tobramycin, amikacin, epinephrine, ephedrine, chlorphenamine, naphazoline, bepotastine, chloramphenicol, travoprost acetylcysteine, , fluorometholone, flurbiprofen, nepafenac, ofloxacin, natamycin, prednisolone, atropine, lifitegrast, sodium hyaluronate, lubricating eye drops for dry eye comprising polymers or lubricating agents such as polyvinyl alcohol, povidone, hyaluronic acid and its salts, polyethylene glycol, propylene glycol, carmellose, methylcellulose and like, or combinations thereof.

In another embodiment, the present invention provides a container for dispensing a preservative free therapeutic composition, comprising:
a) a vessel configured to store the preservative free therapeutic composition,
b) a nozzle, and
c) a cap; wherein the vessel, the nozzle, and/or the cap are impregnated with an antimicrobial agent.

Another embodiment of the present invention provides a container for ophthalmic products, wherein in the container made of polymeric material impregnated with antimicrobials help mitigate issues that could otherwise interfere with the safety and commercial success of the drug product. It is a known concern that conventional preservatives in solution at high concentrations can interfere with the safety and commercial success of a product due to corneal and ocular toxicity of these conventional preservatives. By impregnating, embedding, or surface treating the antimicrobials in the polymeric material offer the potential to provide antimicrobial protection without need of conventional preservatives. Embodiments of the disclosure serve to alleviate possible microbial contamination of ophthalmic containers during repeated use.

In the present invention, “microbes or microorganism or microbial contaminants” means any unicellular or multicellular organism that is pathogenic or parasitic on other organisms such as humans. Microorganisms include molds, fungi, yeasts, bacteria and viruses. The antimicrobial agent according to the present invention may be, for example, an agent which is antibiotic, bactericidal or bacteriostatic, fungicidal, or fungistatic.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and don't limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES

1. Preparation of Container (6 grams):
Preparation of antimicrobial beads of grade GGPT-10 includes approx. 98% of glass oxide and less than 2% of silver. The above-mentioned beads are in form of white powder having particle size i.e. d50 of 8-10 microns.

Table 1:
Polymer Density
(gm/cm3) MFI of polymer (g/10mnts) Antimicrobial Active agent Loading of antimicrobial active agent (%) Processing temperature (0C) Cutting used Type of cutting
Low density polyethylene 0.97-0.99 1.0-2.0 GGPT-10 10 130-200 Co-extruder Strand cutting

The masterbatch has a GGPT loading of 10%, the 10% loaded masterbatch is mixed with container resin at a dosing of 6%. This effectively makes an overall loading of 0.6% of antimicrobial agent in the container’s composition.

2. Anti-Microbial Efficacy Studies:
Methodology used to test the activity of antimicrobial active agent:
1. Preparation of inoculum:
(a) Inoculated the surface of appropriate agar medium (soybean casein digest agar or Sabouraud dextrose agar) from a recently grown stock culture of test microorganisms
(b) Used soybean casein digest agar for Escherichia coli ATCC 8739, pseudomonas aeruginosa ATCC 9027, Staphylococcus aureus ATCC 6538 and incubated at 32.5 ±2.5oC for 3-5 days.
(c) Sabouraud dextrose agar for Candida albicans ATCC 10231 and Aspergillus brasiliensis ATCC 16404 and incubated at 22.5 ± 2.5oC for 3-7 days
(d) harvested the cultures by washing the growth with sterile saline to obtain microbial count of about 1x108 CFU/ml.
2. Series of containers filled with sample, i.e., Preservative free Sodium hyaluronate eye drops 0.1% w/v, were inoculated with cultures mentioned in point (b), point (c) of step 1 (Challenge organisms mentioned in USP chapter<51>), in such a way that each container is inoculated with a suspension of one of the test organisms to give an inoculum of about 105 to 106 microorganism per millilitre or per gram of the preparation.
3. Kept the container with sample and culture for seven days at 25oC and tested.
4. Kept the container with sample and culture for 14 days at 25oC and tested.
5. Kept the container with sample and culture for 28 days at 25oC and tested.

Table 2: Batch 1:
Organism Initial count at dilution 104 After 7 days After 14 days After 28 days
Dilution Colonies Final Count Dilution Colonies Final Count Dilution Colonies Final Count
E.coli 815000 103 39,46 42500 102 2,2 200 102 1,2 150
S.aureus 745000 103 16,14 15000 102 6,7 650 101 0,0 ?10
P.aeruginosa 805000 103 12,9 10500 102 3,2 250 101 2,5 35
C.albicans 585000 103 16,13 14500 102 2,3 250 101 0,0 ?10
A niger 265000 103 2,2 2000 102 1,2 150 101 0,0 ?10

Table 3: Batch 2
Organism Initial count at dilution 104 After 7 days After 14 days After 28 days
Dilution Colonies Final Count Dilution Colonies Final Count Dilution Colonies Final Count
E.coli 815000 103 24,28 26000 102 4,2 300 102 2,1 150
S.aureus 745000 103 9,12 10500 102 3,3 300 101 0,0 ?10
P.aeruginosa 805000 103 13,17 15000 102 2,3 250 101 3,6 45
C.albicans 585000 103 24,26 25000 102 0,0 ?100 101 0,0 ?10
A niger 265000 103 6,3 4500 102 1,2 150 101 0,0 ?10

It is observed that the both batch 1 and batch 2 complies with respect to antimicrobial efficacy test as per acceptance criteria of USP chapter <51>.

3. Specific Test organism (bacteria) used for evaluating antimicrobial activity:
Staphylococcus aureus ATCC 6538
Escherichia coli ATCC 8739
Test method used for testing the activity of antimicrobial agent is JIS Z 2801: 2010

Result 1: Test Bacteria: Staphylococcus aureus ATCC 6538

Table 4:
Untreated: Conc. of Inoculum on untreated sample at 0 hrs (A): 1.49 x 105 Log=5.17
Untreated: Conc. of Inoculum on untreated sample after 24 hrs (B): 1.62 x 106 Log=6.20
Batch Number No. of Bacteria on treated sample (C) Log of Bacteria on treated sample Antimicrobial activity (R) (log B-C) Microbial Kill
(% reduction)
1-1 7200 3.85 2.35 99.55
1-2 13400 4.12 2.08 99.17
1-1 6900 3.83 2.37 99.57
2-2 10100 4.00 2.20 99.37

When tested as specified, it was observed that the antimicrobial agent incorporated in the polymer material of container shows extensive antimicrobial activity by killing more than 99% of Staphylococcus aureus ATCC 6538 in the sample.

Result 2: Test Bacteria: Escherichia coli ATCC 8739

Table 5:
Untreated: Conc. of Inoculum on untreated sample at 0 hrs (A): 1.30 x 105 Log=5.11
Untreated: Conc. of Inoculum on untreated sample after 24 hrs (B): 3.50 x 106 Log=6.54
Batch Number No. of Bacteria on treated sample (C) Log of Bacteria on treated sample Antimicrobial activity (R) (log B-C) Microbial Kill
(% reduction)
1-1 10800 4.03 2.51 99.69
1-2 15900 4.20 2.34 99.54
1-1 7400 3.86 2.68 99.78
2-2 11800 4.07 2.47 99.66

When tested as specified, it was observed that the antimicrobial agent incorporated in the polymer material of container shows extensive antimicrobial activity by killing more than 99.5% of Escherichia coli ATCC 8739 in the sample.

4. Sodium Hyaluronate Eye Drops 0.1% w/v:
Sodium Hyaluronate Eye Drops 0.1% w/v drops comprises:
Sodium Hyaluronate………………………… 0.1% w/v
Sodium chloride ……………………………....0.9% w/v
Sodium Carboxymethylcellulose ……………..0.01% w/v
Buffer………………………………………….0.02% w/v
Sterile aqueous vehicle ………………………..q.s.

5. Stability data of Sodium Hyaluronate Eye Drops 0.1% w/v:

Parameters Batch Initial After 14 days After 28 days Specification limit
pH Batch 1 6.9 7.1 7.12 6.5 to 7.5
Batch 2 6.9 7.0 7.10
Drug Assay
(%) Batch 1 106.24 106.24 106.23 90 to 120
Batch 2 106.23 106.23 106.23
Osmolality
(mOsmol/Kg) Batch 1 258 261 262 250 to 270
Batch 2 257 262 263
Description Batch 1 clear clear clear Clear
Batch 2 clear clear clear

,CLAIMS:We Claim:

1. A liquid dispensing container for dispensing a preservative free pharmaceutical composition, wherein the container is made up of a material impregnated with an antimicrobial agent.

2. The liquid dispensing container as claimed in claim 1, wherein the material is a polymeric material and the antimicrobial agent is embedded in the polymeric material or coated on the polymeric material.

3. The liquid dispensing container as claimed in claim 2, wherein the antimicrobial agent is dispersed and distributed evenly throughout the polymeric material.

4. The liquid dispensing container as claimed in claim 3, wherein the antimicrobial agent includes beads comprising silver, triclosan, zinc, copper, cerium, or their ionic forms, or combinations thereof.

5. The liquid dispensing container as claimed in claim 4, wherein the antimicrobial agent includes beads comprising silver phosphate glass powder having not more than 3.0% of silver.

6. The liquid dispensing container as claimed in claim 1, wherein the antimicrobial agent includes beads comprising silver phosphate glass powder and wherein the silver is present in the container in an amount between = 20 µg/g to = 110 µg/g.

7. The liquid dispensing container as claimed in claim 2, wherein the polymeric material is selected from the group comprising low density polyethylene, high density polyethylene, high impact polystyrene, polypropylene, polystyrene, polyethylene terephthalate, polyvinyl chloride, polycarbonate, or combinations thereof.

8. The liquid dispensing container as claimed in claims 5 and 6, wherein the silver phosphate glass powder has a particle size d50 less than 50 microns.

9. The liquid dispensing container as claimed in claim 1, wherein the container
comprises:
a) a vessel configured to store the preservative free pharmaceutical composition,
b) a nozzle, and
c) a cap; and wherein the vessel, the nozzle, and optionally the cap is made up of the material impregnated with the antimicrobial agent.

10. The liquid dispensing container as claimed in claim 9, wherein the preservative free pharmaceutical composition is sterile and is for ophthalmic use.

Dated 9th Day of Dec, 2022 For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer