INTRODUCTION:
Eye is the most simply reachable site for topical administration of a medication. Drugs are commonly applied to the ocular system for a localized action on the surface or in the interior of the eye. The ocular system is most interesting organ due to its drug disposition characteristic1.
Conventional ophthalmic delivery systems like eye drops result in poor ocular drug bioavailability due to ocular anatomical and physiological constraints, which include the relative impermeability of the corneal epithelial membrane, tear dynamics and nasolacrimal drainage. Most of the topically applied drugs are washed off from the eye by various mechanisms include lacrimation, tear dilution and the residence time of most conventional ocular solutions ranges between 5 and 25 minutes. Only 1-10% of topically applied drug is absorbed, and major part of drug absorbed systemically results in systemic side effects2-4.
Repeated applications of eye drops can cause biochemical and mechanical injuries as well as sensitivity reactions resulting in blepharo conjunctivitis. Frequent local instillation of antigluacoma agents, antibiotics, antiviral and sulphonamide provide an unusual high drugs and preservative concentration at epithelial surface. To improve the ocular bioavailability and reduce the local and systemic side effects the need to formulate the controlled ocular delivery arises. Hence, an attempt is made to localize and control the drug release and activity at the site of action5,6.
Newer ocular delivery systems are being explored to develop extended duration and controlled release strategy. The main objective of ophthalmic inserts is to increase the contact time between preparation and the conjunctival tissue to ensure controlled release suited to topical/systemic treatment.
Ocular inserts are defined as preparations with a solid or semisolid consistency, whose size and shape are especially designed for ophthalmic application (i.e., rods or shields). These inserts are placed in the lower fornix and, less frequently, in the upper fornix or on the cornea. They are usually composed of a polymeric vehicle containing the drug and are mainly used for topical therapy. Ocular inserts offer several advantages which can be summarized as follows (i) Increased ocular residence, hence a prolonged drug activity and a higher bioavailability with respect to standard vehicles; (ii) Possibility of releasing drugs at a slow, constant rate; (iii) Accurate dosing and reduction of systemic absorption; (iv) Better patient compliance, resulting from a reduced frequency of administration and a lower incidence of visual and systemic side-effects; (v) Possibility of incorporating various novel chemical/technological approaches7,8.
Ciprofloxacin hydrochloride monohydrate is a synthetic fluoroquinolone antibacterial agent. It is rapidly active against Gram-negative aerobic bacteria including Enterobacteriaceae, Pseudomonas aeruginosa, Haemophilus, and Neisseriae. It is also active against many Gram-positive aerobic pathogens including penicillinase-producing and methicillin-resistant Staphylococci. Ciprofloxacin acts by inhibiting the DNA synthesis of the microorganism9. It is presently available as an eye drops 0.3%. It is administered 1-2 drop into the affected eye every four hours10. So in the present delivery system, we aimed to find the right ratio of polymer to control the rate of release of Ciprofloxacin from ocuserts.
MATERIAL AND METHODS:
Preparation of ocular inserts:
The ocular inserts wear prepared by solvent casting method. The inserts were prepared by solvent casting method. The required quantity of the polymer HPMC and PVA in a different ratio was weighed and dissolved in distilled water by gentle stirring. The Glycerol (10% solution in distilled) was added as plasticizer to above solution under stirring condition. The prepared 0.3% solution of Ciprofloxacin was added in polymer solution and stirred 30 minutes to get a similar dispersion. After complete mixing, the casting solution was poured into clean petridish, and covered with an inverted funnel to allow slow and uniform evaporation at room temperature. The petridish was dried at room temperature for 24 hr. The dried films thus obtained were cut into circular pieces (10 mm) by the help of cork borer and stored until used11,12. The composition of different formulation of Ciprofloxacin is given in table 1.
Table 1: Composition of Ciprofloxacin ocuserts
|
Ingredients |
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
|
Ciprofloxacin (%W/V) |
0.3 |
0.3 |
0.3 |
0.3 |
0.3 |
0.3 |
|
HPMC (%W/V) |
0.5 |
- |
0.5 |
0.5 |
1.0 |
1.0 |
|
PVA (%W/V) |
- |
0.5 |
0.5 |
1.0 |
0.5 |
1.0 |
|
Glycerol |
0.2 ml |
0.2 ml |
0.4 ml |
0.6 ml |
0.6 ml |
0.8 ml |
|
Distilled water |
10 ml |
10 ml |
10 ml |
10 ml |
10 ml |
10 ml |
Evaluations of prepared formulations:
Uniformity of weight:
For determination of ocular inserts uniformity, twenty ocular inserts were taken from each batch and different areas of the film and weighed individually on electronic balance. Mean weight of inserts of each formulation was recorded. The mean were then calculated.
Content uniformity:
To check the uniformity of the drug in the circular film, five ocular inserts were taken out from each film. Each inserts were then placed in beaker containing 10 ml of isotonic phosphate buffer pH 7.4 and dissolved and were filtered into 25 ml volumetric flask and the volume was made up to the mark with phosphate buffer. One ml of the above solution was withdrawn and the absorbance was measured by UV-VIS spectrophotometer at 288 nm with against blank.
Surface pH:
Surface pH of the inserts was determined by allowing them to swell in a closed Petri dish at room temperature for 30 min in 0.1 ml of distilled water. The swollen devices were removed and placed on Pen pH meter to found surface pH.
Swelling index:
Three films were weighed and placed separately in beakers containing 4 ml of distilled water. At regular intervals of time (every 10 min), the films were removed and the excess water on their surface was removed using a filter paper and then again weighed. The procedure was continued till there was no increase in the weight. The ocular inserts was swelled and increased in the weight at 50 minutes. The swelling index was then calculated by using formula.
Swelling Index (Sw) %= [wt - wo/wo] ×100
(Sw)%= equilibrium percent swelling, wt: weight of swollen insert after time t, wo: original weight of insert at zero time
% Moisture absorption:
The prepared ocular inserts was accurately weighed and placed in a desiccators containing aluminium chloride it was kept for 3 days. The ocuserts was taken out and reweighed after 3 days. The amount of moisture absorbed by the ocular inserts was calculated by using the following formula62.
% Moisture loss:
The films were weighted and kept in desiccators containing anhydrous calcium chloride. After three days, the films were taken out and reweighed. The percentage moisture loss was calculated using the following formula54.
In-vitro diffusion study:
Static Franz glass diffusion cells have been used in order to evaluate the release profile. These cells consist of donor and acceptor chambers between which a diffusion membrane is positioned. Cellulose nitrate membranes used with an average pore size of 0.1 μm were used. The study was carried out in 50 ml of Phosphate buffer solution (7.4 pH). The dissolution medium was maintained temperature at 37±0.5oC. At predetermined time intervals 1 ml of sample were withdrawn and replaced with fresh media. The The sample was analyzed for the drug content using UV spectrophotometer at 288 nm13-17.
RESULT AND DISCUSSION:
The ocular inserts of Ciprofloxacin were prepared by solvent casting technique and distinguished on the basis physico-chemical characteristics, and in vitro release studies.
The physicochemical evaluation data presented in table 2 indicates that the thickness of the ocular inserts films vary from 0.162±0.07 mm to 0.473±0.05 mm. Thickness of ocuserts slightly increased as the concentration of HPMC and PVA increased. Each preparation displayed similar thickness with low standard deviation values ensuring the homogeneity of the films prepared by film casting method. Those being the case formulations were not thick enough to produce any irritation while placing and being in cul-de-sac.
The findings showed that weights of formulations were ranging from 5.85±0.04 mg to 8.29±0.08 mg for ocular inserts films. This reveals that there was no relevant weight diversity in all formulations.
The percentage moisture absorption and moisture loss was also influenced by polymer used in the insert preparation. The results indicate that the moisture absorption and moisture loss were varied from 5.12±0.12% to be 8.16±0.18% and 4.86±0.41% to 7.91±0.09% respectively. Increment in amount of PVA in formulation raised swelling, which may be due to its solubility in water. The moisture absorption was carried out to check the physical stability or integrity at wet condition. The percentage moisture loss was carried out to check the integrity of the film at dry condition.
Each of the formulations was subjected to assess the surface pH. They possessed pH near to neutral pH and hence will not produce any difficulty or irritation while placing in the cul-de-sac of the eye. The results showed that percentage swelling index of formulations were ranging from 7.35±0.62 to 16.18±0.84 for ocular inserts films. This reveals that increase in amount of HPMC and PVA in formulation raised in percentage swelling index of ocular insert. For the various formulations drug content uniformity was found to vary between 71.25±3.47% to 85.65±4.25%. The formulation F2 showed least drug content (71.25±3.47).
At different time interval sample was withdrawn and cumulative percentage drug released in mg was calculated, on the basis of mean amount of Ciprofloxacin present in the respective films. The table 3 and figure 1 revealed that formulation F4 and F5 showed a maximum cumulative percentage drug release of 100.0% at the end of 12 hours, followed by the other formulations F6 (83.6 %). While the formulations F1 and F2 release maximum drug before 8 hours, moreover F3 release maximum drug of 100% at the end of 10 hours. From the result it was observed that formulation F4 and F5 shows good physicochemical parameters as compared to other formulations. As results indicated that the % cumulative release for ocular insert F4 and F5 was 100% at the end of 12 hours and hence found to be appropriate for therapy. Ocuserts can be converted to a promising marketable product in the category of ophthalmic products.