Relief Protection Balance

Transcription

1 Relief Protection Balance

2 Sensations of ocular dryness Sensations of ocular dryness are common and debilitating. They are often accompanied by other symptoms, such as: feelings of soreness, fatigue, burning, itching or grittiness in the eyes photosensitivity blurred vision tearing These sensations of ocular dryness occur as a result of 2 mechanisms: the precorneal tear film becomes unstable and breaks up more rapidly than is normal, leaving areas of the cornea uncovered (Fig.1a, b) the osmolarity of the preconeal tear film increases (tear hyper-osmolarity), leading to loss of surface lubrication and to ocular surface damage This usually happens because of a deficiency in the aqueous component of the tear film or an increase in tear evaporation, or a combination of these events. The precorneal tear film is a complex coating with several important functions: lubrication of the surface of the eye maintenance of a moist environment on the surface of the eye maintenance of a smooth refracting surface on the cornea provision of the cornea with nutrients and oxygen prevention of bacterial infection protection against foreign bodies Sensations of ocular dryness have a variety of causes. Many cases are due to environmental factors, examples being: air conditioning or heating bright lights smoky, polluted or dusty air windy or dry conditions ther causes include extended working at a computer screen and the use of contact lenses. External lipid layer Intermediate aqueous layer Corneal stroma External lipid layer Intermediate aqueous layer Corneal stroma Dry spot Internal mucous layer Epithelial cells Internal mucous layer Epithelial cells Fig. 1a: Normal precorneal tear film Fig. 1b: Precorneal tear film in patients with sensations of ocular dryness 2

3 VISMED is a unique product that has been developed specifically for the treatment of sensations of ocular dryness. It is presented as lubricant eye drops in boxes of 2 (or 6) preservative-free, sterile single dose units (Fig. 2). VISMED is a hypotonic aqueous solution of sodium hyaluronate (SH) which contains a number of important ions also found in natural tears, and, as such, is very close in characteristics to the natural tear film. The inclusion of both SH and essential ions in VISMED is possible because of its unique patented formulation with citrate. With this special formulation, VISMED offers patients with sensations of ocular dryness an unmatched combination of symptomatic relief and comfort. VISMED : Relief VISMED is highly effective in relieving symptoms associated with sensations of ocular dryness VISMED can aid the healing of superficial keratitis VISMED increases tear film break-up time (BUT) VISMED is comfortable in the eye VISMED : Protection VISMED coats the cornea effectively SH solutions adhere well to the mucin layer of the tear film. Therefore, the coatings formed by such solutions are long-lasting The physical properties of SH solutions are similar to those of the natural tear film SH is highly effective in entrapping water. Therefore, evaporation of water from SH solutions is slow, and the beneficial effects of such solutions are prolonged VISMED : Balance Fig. 2: VISMED box of 2 SDUs VISMED is hypo-osmolar relative to natural tears, as the tear film is hyper-osmolar in many patients with sensations of ocular dryness VISMED contains ions that are essential for the maintenance of corneal functions VISMED is preservative-free VISMED has a ph of similar to that of natural tears The formulation of VISMED has been carefully balanced to ensure that both efficacy and tolerability are optimised 3

4 Sodium hyaluronate SH is the sodium salt of hyaluronic acid, a naturally occurring biopolymer that has important functions in many parts of the body. It is a glycosaminoglycan consisting of repeating disaccharide units of N-acetyl- D-glucosamine and sodium-d-glucuronate (Fig. 3) 1. C 2 - CH 2 H H H NH H C= CH 3 n.na Fig. 3: Chemical structure of sodium hyaluronate Solutions of SH have been used for many years in ophthalmic surgery, to maintain the shape of the eye, to cover surgical instruments and to protect the corneal endothelium from damage. They have unique physical properties that make them ideal for use in the treatment of sensations of ocular dryness 2. The most important property of SH solutions is their viscoelasticity; this property allows such solutions, when instilled into the eye, to behave differently during and between blinks 3,4. During blinks, shear stress causes the molecules of SH in a solution to align with one another (Fig. 4a). As a result, the solution becomes elastic and relatively non-viscous, and spreads easily over the surface of the cornea. Between blinks, the molecules of SH form a tangled meshwork, and the solution becomes less elastic and more viscous (Fig. 4b). Consequently, the precorneal tear film is stabilised and the residence time of the solution on the surface of the eye is maximised. The SH in VISMED has several specific features that help to maximise the efficacy and tolerability of this product: It is obtained by bacterial fermentation and is therefore free from potentially allergenic animal proteins It is highly purified It is present at a concentration of.18% - nearly twice the concentration of.1% that has been shown to be the minimum necessary for efficacy in the treatment of sensations of ocular dryness 5 It has an average molecular weight of 1.2 million daltons and a narrow molecular weight range Fig. 4a: While blinking, SH molecules align and spread easily over the eye surface. Fig. 4b: Between blinks, SH forms a long-lasting protective coating. 4

5 VISMED : Relief Symptomatic relief The efficacy of VISMED in relieving both the intensity and frequency of symptoms associated with moderate sensations of ocular dryness has been assessed in a double-masked, phase III trial involving 15 patients 6. In this trial, the patients were randomised to receive VISMED or.9% saline 3 times per day for 28 days. The results show that VISMED provided significantly (p<.25) superior symptom relief compared with saline over 7 and 28 days (Fig. 5a). Weighted VAS-Sumscore Change from baseline Composite index of symptoms intensity and frequency VISMED Saline p< Days Fig. 5a: VISMED is effective in relieving symptoms Healing of cornea and conjunctiva Additional results from the trial described above demonstrate that VISMED provided significantly (p<.25) greater healing of the cornea and conjunctiva compared to saline (Fig. 5b) 6. VISMED forms a protective coating over the eye surface, thereby preventing further damage and allowing the natural healing process to occur more rapidly. Stabilisation of the tear film Data from a comparative, cross-over, phase IIa study involving 15 patients with moderate sensations of ocular dryness show that the instillation of a single drop of VISMED led to a significant (p<.5) increase in the break-up time (BUT) that lasted for more than 6 hours (Fig. 6) 7. The increase in BUT was significantly (p<.5) superior to that of.9% saline after 5, 15, 3 minutes and 2, 3, 4, 5 and 6 hours. Difference from baseline (sec) 1 5 to 6 hours follow up Minutes Comfort In another study 8, a total of 16 out of 32 patients (5%) in the carbomer group experienced blurred vision upon instillation of the product, whereas only 2 out of 32 (6.3%) in the VISMED group reported this sensation. This difference was significant (p<.1) in favour of VISMED. In this respect, VISMED was considered more comfortable than carbomer by the patients (Fig. 7). VISMED Saline p<.5 Fig. 6: VISMED increases tear film BUT more than saline Lissamine green staining Change from baseline VISMED Saline p<.25 Percentage of patients with blurred vision Days carbomer Blurred vision No blurred vision VISMED p<.1 Fig. 5b: VISMED accelerates the natural healing process Fig. 7: VISMED is comfortable to use. 5

6 VISMED : Protection Angle of contact Due to its low angle of contact 7, Vismed is highly effective in coating the cornea (Fig. 9, 1). The low angle of contact of Vismed is achieved through the correct balance of molecular weight and concentration. Product VISMED SH.18%, MW 1.2 million Da SH.1%, MW 2.5 million Da Sodium CMC 1% Fig. 1: VISMED has a low angle of contact Mucoadhesivity SH solutions adhere well to the mucin layer of the precorneal tear film. As a result, such solutions coat the cornea effectively and the coatings they form are long-lasting. The mucoadhesive properties of SH solutions have been demonstrated in a study 9 in which SH solutions were found to be markedly more mucoadhesive than poly(acrylic acid) hydrogels (Fig. 11). α Mucomimesis The precorneal tear film has viscoelastic properties, which are determined largely by the mucus it contains 1. These properties are mimicked closely by SH in VISMED. The physical similarity between the tear film and SH solutions is believed to contribute to the efficacy and tolerability of these solutions when they are used as lubricant eye drops 1. Water retention SH is highly effective in taking up and retaining water 11,12. Because of this, evaporation of water from SH solutions used as lubricant eye drops is slow, and the beneficial effects of such solutions are prolonged (Fig. 12). C α Fig. 9: Angle of contact (α) H CH 2 H H H C CH 3 NH Index of mucoadhesion at ph 7.4 (detachment force/area, N/m2) (mean +/- 95% CL) Sodium hyaluronate solution Poly(acrylic acid) hydrogel (5%) 5% 15% kda 134 kda kda kda kda kda H H C NH CH 3 H Fig. 12: SH has a polymeric structure that binds a large amount of water H C H CH 2 H Fig. 11: SH solutions are mucoadhesive 6

7 VISMED : Balance Hypo-osmolarity The osmolarity of the tear film is usually about 3 msm/l, but may be as high as 34 msm/l in patients with sensations of ocular dryness Tear film hyper-osmolarity is believed to make an important contribution to the discomfort felt by patients with sensations of ocular dryness, and experiments in animal models indicate that it may also be responsible for the corneal abrasion seen in many of these patients 16. In view of the problems associated with tear film hyper-osmolarity, VISMED has been formulated to be hypo-osmolar, and has an osmolarity of 15 msm/l. In a randomised, comparative, phase II trial, VISMED has been shown to be significantly (p<.5) more effective than isotonic.3% HPMC in reducing tear film osmolarity in patients with moderate sensations of ocular dryness (Fig. 13) 17. Essential ions Among other ions, VISMED contains calcium, magnesium and potassium. These ions are found in natural tears and play an essential role in maintaining the correct function of the cornea: calcium and magnesium are important in cell adhesion, cell junctions and cellular transport, and potassium contributes to the maintenance of corneal thickness 18, 19. The concentrations of these ions in VISMED are similar to those in natural tears. smolarity (msml/l) min after instillation VISMED HPMC p<.5 Baseline D15 D3 D6 Days Fig. 13: VISMED (15 msm/l) reduces tear film osmolarity Preservative-free VISMED is completely free from preservatives. As a result, it is non-irritating to ocular tissues and can be used frequently and for extended periods without harming the surface of the eye (e.g. without causing superficial punctate keratitis). Some preservatives are known to cause toxic or allergic reactions, the symptoms of which include stinging, burning and redness of the eyes 18. Physiological ph The ph of VISMED is adjusted to similar to that of the natural tear film. Numerous studies have shown that, to maximise tolerability, solutions instilled into the eye should be neutral or slightly alkaline 21. Citrate VISMED contains sodium citrate in his patented formulation for the solubilisation of essential ions and the maintaining of HA viscoelastic properties. It prevents also precipitation of other ions 2. 7

8 Relief, Protection & Balance K!S - GENEVA - CH /8 VISM-3b References 1 Meyer K. Chemical structure of hyaluronic acid. Fed Proc 1958; 17: Abelson MB, Mally L, usler G. Dry eye today and tomorrow. Rev phthalmol 2; part 1: Bron AJ. Prospects for the dry eye. Trans phthalmol Soc UK 1985; 14: Tiffany JM. Viscoelastic properties of human tears and polymer solutions. Adv Exp Med Biol 1994; 35: Hamano T, Horimoto K, Lee M, Komemushi S. SH eyedrops enhance tear film stability. Jpn J phthalmol 1996; 4: Baeyens V, Baudouin C, Dorsey F, and the French VISMED Study Group. Efficacy and safety of SH.18% vs. sodium chloride.9% in patients with bilateral moderate dry eye. Invest phthalmol Vis Sci 24. (poster presented at ARV 24). 7 TRB Chemedica International SA: Data on file. 8 Johnson M, Murphy PJ, Boulton M. Carbomer and sodium hyaluronate eyedrops for moderate dry eye treatment. ptometry and Vision Science, in press. 9 Saettone MF, Chetoni P, Torracca MT, Burgalassi S, Giannaccini B. Evaluation of mucoadhesive properties and in vivo activity of ophthalmic vehicles based on hyaluronic acid. Int J Pharm 1989; 51: Tiffany JM. Composition and biophysical properties of the tear film: knowledge and uncertainty. Adv Exp Med Biol 1994; 35: Balazs EA, Band P. Hyaluronic acid: its structure and use. Cosmetics Toiletries 1984; 99: Nakamura M, Hikida M, Nakano T, Ito S, Hamano T, Kinoshita S. Characterization of water retentive properties of hyaluronan. Cornea 1993; 12: Verges C, Refojo MF, Gilbard JP, Kenyon KR. Effect of hyper-osmolarity on conjunctival goblet cell density in vivo. Invest phthalmol Vis Sci 1984; 25 (Suppl): Gilbard JP. Human tear film electrolyte concentrations in health and dry-eye disease. Int phthalmol Clin 1994; 34: Gilbard JP, Kenyon KR. Tear diluents in the treatment of keratoconjunctivitis sicca. phthalmology 1985; 92: Gilbard, Carter JB, Sang DN, Refojo MF, Hanninen LA, Kenon KR. Morphologic effect of hyper-osmolarity on rabbit corneal epithelium. phthalmology 1984; 91: Rapisarda A, Battaglia F, Bossy L. Efficacy and safety of hypotonic.18% SH solution (Vismed )in patients with moderate dry eye -A study of the osmolarity of the tear film. Poster presented at the ISPT Reddy IK, Aziz W, Sause RB. Artificial tear formulations, irrigating solutions and contact lens products. In: Reddy IK (ed). cular therapeutics and drug delivery. A multidisciplinary approach. Basel: Technomic Publications, 1996: Green K, MacKeen DL, Slagle T, Cheeks L. Tear potassium contributes to maintenance of corneal thickness. phthalmic Res 1992; 24: Aleo D, Bossy L. Considerations on the risk of precipitation of calcium phosphate salts following the use of Vismed (.18% SH) formulation. Poster presented at the ISPT Gangrede NK, Gaddipati NB, Ganesan MG, Reddy IK. Topical ophthalmic formulations: basic considerations. In: Reddy IK (ed). p cit; Prescribing information Intended use: Sensation of dryness and other minor complaints of no pathological significance, such as burning and ocular fatigue induced, for example, by dust, smoke, dry atmosphere, air conditioning, extended computer screen use or contact lens wear. Composition Active ingredient: Sodium hyaluronate. Excipients: Sodium chloride, potassium chloride, disodium-hydrogen-phosphate, sodium citrate, magnesium chloride, calcium chloride and water for injection. The solution is hypotonic (15msm/l) adjusted to ph 7.3. Presentation: Sterile single dose units of.3 ml containing.18% SH for topical ophthalmic use. VISMED is preservative-free. Dosage and administration: Twist off tab. If not otherwise recommended, place one or two drops into the conjunctival sac of the eye as often as needed. A sensation of blurred vision may be experienced immediately after application, as VISMED spreads over the eye. This will quickly disappear as the solution forms a long lasting and transparent coating on the surface of the eye. VISMED may also be used while wearing contact lenses (rigid or soft). As VISMED does not contain preservatives, any solution not used immediately after opening should be discarded. Characteristics and mode of action: VISMED contains a highly purified specific fraction of SH derived by fermentation from bacteria. SH is a natural polymer which is also present in the structures of the human eye. Its main physical characteristic is viscoelasticity. This means that VISMED has a high viscosity between blinks and low viscosity during blinking ensuring efficient coating of the surface of the eye. This protective coating of the surface of the eye helps prevent dryness and irritation. SH also possesses mucoadhesive properties and the ability to entrap water, thus resembling tear mucus glycoprotein. This, together with the coating properties of SH results in an increased precorneal residence and tear film break-up time (BUT) and therefore longer lubrication of the corneal surface. VISMED has been uniquely formulated to contain citrate in order to maintain its viscoelastic properties in the presence of other ions. The hypertonicity of altered tear fluid has been implicated in corneal abrasions. The hypotonicity of VISMED compensates for the hypertonicity of altered tear fluid thus limiting corneal damage. Biocompatibility: Results of acute, sub-acute and chronic toxicity studies together with the results of the foetal toxicity, fertility, peri-and post-natal toxicity studies show that SH is very well tolerated. In addition, animal studies show that repeated topical ocular administration of VISMED is also well tolerated. In clinical use, no adverse effects were observed. Interactions: Do not use VISMED at the same time as any other drug or product applied to the eye since it may modify their effects. Storage: Store between 2 C and 25 C, in original sachet and box, away from heat sources and light. Shelf-life: 3 years if stored in original package. Packaging: VISMED is presented in boxes of 2 (or 6) single dose units. Each box contains a heat-sealed polyethylene-aluminium sachet containing 4 strips of 5 single dose units. TRB CHEMEDICA INTERNATINAL SA Geneva - Switzerland Tel Fax international@trbchemedica.com Manufacturer: TRB CHEMEDICA AG Haar/Munich Germany