Methods of diagnosing and treating dry eye syndrome and compositions for treating a human eye

Abstract

In preferred embodiments the invention is directed to ocular compositions for the treatment of dry eye, methods for making such compositions, and suites comprising a plurality of different ocular compositions each having a defined composition. In preferred examples, the invention is directed to compositions comprising at least one natural oil, wherein a first member of the suite of compositions is effective in treating dry in in a first patient having a particular set of symptoms and a different second member of the suite of compositions is effective in treating dry in in a second patient having a different set of symptoms. The invention is also directed to methods of making and using the compositions, and to skin care compositions for use around the eye, such as the upper and lower eyelids having a lubricating, non-irritating base composition comprising at least one natural oil.

Claims

1. A composition for applying to an eye or eyelid of a human comprising: water; and 0.1% (w/v) to 0.3% (w/v), inclusive, of a hydrophobic component, wherein the hydrophobic component comprises from about 0.05% (w/v) to about 0.25% (w/v) avocado oil and from about 0.05% (w/v) to about 0.25% (w/v) castor oil, and at least one additional component selected from the group consisting of: an emulsifier component, a surfactant component, a tonicity component, a polyelectrolyte component, an emulsion stability component, a viscosity-enhancing component, a demulcent component, an anti-oxidant component, a pH adjustment component, a buffer component, and a preservative component, the hydrophobic component being present in an amount effective to provide a benefit to an eye or eyelid of a human.

2. The composition of claim 1 in which said at least one additional component comprises a first viscosity-enhancing component having a negative charge.

3. The composition of claim 2 in which said at least one additional component further comprises a emulsion stability component.

4. The composition of claim 3 in which said first viscosity-enhancing component comprises a polymer of acrylic acid, and the emulsion stability component is a non-ionic surfactant.

5. The composition of claim 1 containing a) from about 0.05% to about 0.01% by weight of a crosslinked co-polymer of acrylic acid and alkyl acrylate, and b) from about 0.05% to about 1.5% by weight of a non-ionic surfactant.

6. The composition of claim 1 wherein the viscosity-enhancing component comprises a cellulose polymer selected from the group consisting of carboxymethyl cellulose (CM), methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), and hydroxypropyl cellulose.

7. The composition of claim 1 comprising, by weight, between about 0.5% and about 1% glycerin; between about 0.05% and about 1.5% polysorbate 80; between about 0.01% and about 0.05% of a crosslinked co-polymer of acrylic acid and alkyl acrylate; between about 0.01% and about 0.1% hydroxypropylmethyl cellulose; between about 0.25% and about 1.2% boric acid; and about 0.1% disodium ethylenediamine tetracetic acid (EDTA).

8. The composition of 7 wherein the avocado oil and the castor oil are each present at a concentration of about 0.05% by weight.

9. The composition of claim 8 wherein a biocidal agent is not present.

10. The composition of claim 8 further comprising a biocidal agent.

11. The composition of claim 1, wherein the at least one component comprises a tonicity component, a viscosity enhancing agent, and a surfactant.

12. The composition of claim 1, wherein the at least one component comprises glycerin, a crosslinked co-polymer of acrylic acid and alkyl acrylate, a hydroxypropyl methylcellulose, a non-ionic surfactant, and benzalkonium chloride.

13. The composition of claim 1 having a viscosity between about one 1.0 centipoise (cP) and about 2000 cP.

14. The composition of claim 13 having a viscosity less than about 250 cP.

15. The composition of claim 13 having a viscosity between about 250 centipoise (cP) and about 2000 cP.

16. The composition of claim 1 in which the avocado oil is present at a concentration of from about 0.05% (w/v) to about 0.1% (w/v).

17. The composition of claim 1 in which the castor oil is present at a concentration of from about 0.05% (w/v) to about 0.1% (w/v).

18. The composition of claim 1 in which the avocado oil is present at a concentration of about 0.05% (w/v) to about 0.1% (w/v) and the castor oil is present at a concentration of about 0.05% (w/v) to about 0.1% (w/v).

19. The composition of claim 1 comprising an artificial tear.

20. The composition of claim 1 comprising an eyelid treatment composition.

21. The composition of claim 1, wherein the at least one additional component comprises a viscosity enhancing agent.

22. The composition of claim 21, wherein the viscosity enhancing agent comprises methylcellulose (MC), carboxymethylcellulose (CMC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), hyaluronic acid salts, or combinations thereof.

Description

(1) Example 1

(2) A series of different artificial tear treatment compositions are prepared. Each of the treatment compositions in accordance with the present invention are suitable for use in treating dry eye syndrome in humans.

(3) TABLE-US-00004 TABLE 1 Compositions w/v % Component G H I J K L M N Jojoba Oil 0.1 — — — 0.25 — 0.1 0.1 Avocado Oil — 0.1 — — — 0.25 0.1 0.1 Tonicity 0.68 0.68 0.68 0.68 0.68 0.68 0.68 0.68 NaCl (or q.s. ad 280 to 320 mOmol Polysorbate 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 80 Glycerin 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Pemulen ® 0.005 0.005 0.005 0.005 0.01 0.01 0.01 0.01 Carbopol ® — — — — — — — 0.25 980 HPMC 0.1 0.1 — — 0.25 0.25 0.25 — Natural Oils: — — — — 0.1 — 0.1 0.1 Argan or Oleuropein PEG 400 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 NaOH/HCl Adjust pH to 7.3 (spec. 7.2-7.4) Boric Acid 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 Na Borate 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 Decahydrate BAK 0.005 0.005 0.005 0.005 0.005 0.005 0.005 — Na Chlorite — — — — — — — 0.005 Purified q.s. ad 100 water (or WFI)

(4) As can be seen above, in certain of the exemplified compositions (e.g., Compositions G, H and L) a single oil is used, while in other compositions (Compositions K, M and N) more than one oil is used, and in still others (Compositions I and J) no oil is used. Thus, a variety of dry eye therapeutic compositions may be made, each to suit a different set of patient symptoms and tear properties. While all the compositions exemplified here contain an antimicrobial (BAK or sodium chlorite), it will be understood that preservative-free (for example, sterile) versions of these or other compositions can also be made). The concentration of viscosity inducing components (in this case compounds such as Carbopol®, Pemulen®, HPMC and PEG) can be varied as needed.

(5) Although the compositions of the present invention are not limited thereto, in preferred examples the range of viscosities of the series of therapeutic compositions is about 3, 5, 7, 10, 15 and 20 centipoise (cP), the specific gravity of each of the compositions is between about 0.7 and about 1.1; the refractive index of each of the compositions is between about 1.20 to about 1.8, with a most preferred range being about 1.33-about 1.57.

(6) Example 2

(7) A group of patients, each of whom is indicating that he/she is experiencing some degree of eye discomfort, are assembled selected for testing to determine the presence or absence of dry eye syndrome.

(8) The testing is conducted by qualified medical personnel who are experienced in recognizing the presence and severity of dry eye syndrome in a patient's eye(s). Tears are collected from, the amount of tears determined, and quality of the tears are analyzed for pH, osmolality, protein content, hydrophobic/hydrophilic balance, and viscosity and compared to average values for subjects unaffected by dry eye syndrome.

(9) As a result of this testing, it is determined that some of the people do not have dry eye syndrome and that others do have dry eye syndrome. In particular, among the people who are identified as having dry eye syndrome subgroups can be identified.

(10) Subgroup A patients have subnormal quantity of tears, but normal levels of protein, indicating that the mucoid (viscous) layer of the tears is intact, an osmolality on the normal range, a normal ratio of hydrophobic to hydrophilic components in the tears, and a pH about 7.4. Based on these findings, an artificial tear treatment composition having the approximate pH, osmolality, ratio of hydrophobic to hydrophilic components, and viscosity of natural tears is preliminarily concluded to be potentially optimal, from the point of view of both effective treatment and patient comfort.

(11) Subgroup B patients have subnormal quantity of tears and protein, and the viscosity of the tears is subnormal. The osmolality of the tears is in the normal range, and there is a normal ratio of hydrophobic to hydrophilic components in the tears, and a pH about 7.4. The patients report a gritty feeling in the eyes. Based on these findings, an artificial tear treatment composition having the approximate pH, osmolality, ratio of hydrophobic to hydrophilic components, and of natural tears, and increased viscosity compared to normal tears (thus permitting the tears to spread more evenly across the cornea), is preliminarily concluded to be potentially optimal, from the point of view of both effective treatment and patient comfort.

(12) Subgroup C patients have subnormal quantity of tears. Protein and viscosity of the tears is also normal. The osmolality of the tears is equivalent to about 1.8% (w/v) sodium chloride (hypertonic). There is a normal ratio of hydrophobic to hydrophilic components in the tears; however the pH of the tears is about 6.2. The patients report a stinging sensation in the eyes. Based on these findings, an artificial tear treatment composition buffered to physiological pH (approximately 7.4) and having the approximate ratio of hydrophobic to hydrophilic components of natural tears, and slightly hypotonic (e.g., equivalent to about 0.5% (w/v) sodium chloride) compared to normal tears, is preliminarily concluded to be potentially optimal, from the point of view of both effective treatment and patient comfort.

(13) Subgroup D patients have normal quantity of tears. Protein and viscosity of the tears is also normal. The osmolality of the tears is equivalent to about 0.5% (w/v) sodium chloride (hypotonic). There is a higher than normal ratio of hydrophobic to hydrophilic components in the tears; pH of the tears is about 7.4. The patients report a stinging sensation in the eyes. Based on these findings, an artificial tear treatment composition having a normal ratio of hydrophobic to hydrophilic components of natural tears, and slightly hypertonic (e.g., equivalent to about 1.8% sodium chloride) compared to normal tears, is preliminarily concluded to be potentially optimal, from the point of view of both effective treatment and patient comfort.

(14) Subgroup E patients have normal quantity of tears. Protein and viscosity of the tears is suboptimal. The osmolality of the tears is equivalent to about 0.5% (w/v) sodium chloride (hypotonic). There is a higher than normal ratio of hydrophobic to hydrophilic components in the tears; pH of the tears is about 7.4. The patients report a stinging, burning sensation in the eyes. Based on these findings, an artificial tear treatment composition having a viscosity slightly higher than normal, a normal ratio of hydrophobic to hydrophilic components of natural tears, and being slightly hypertonic (e.g., equivalent to about 1.8% sodium chloride) compared to normal tears, is preliminarily concluded to be potentially optimal, from the point of view of both effective treatment and patient comfort.

(15) Each member of the group of dry eye syndrome-positive patients is are interviewed regarding their eyes, in particular, whether their eyes are sensitive to anything, including medications and eye drops placed in the eye, whether any allergies and/or other sensitivities are known which could impact the treatment approach to dealing with dry eye syndrome.

(16) These inquiries are sufficiently detailed to identify any specific issues that may arise or become apparent during the treatment of the person's dry eye syndrome. As a result of inquiring of the people in this manner, each of the people are identified as: (a) a person who has only minor or no comfort issues having eye drops in the eye; (b) a person who has significant comfort issues in having eye drops in the eye.

(17) As a result of the above-noted testing and inquiring, each person who was tested and inquired about, as noted above, is provided with one of the Compositions A-E based on the results of the testing and inquiries.

(18) The use of such a testing/inquiry approach, in combination with different treatment compositions, e.g., Compositions A-E, to treat dry eye syndrome provides a highly effective approach to treat dry eye syndrome in a way which is individually selected to treat the dry eye system while, at the same time, taking into account comfort and safety concerns of the person being treated.

(19) Example 3

(20) A set of different ocular skin care base compositions O through Y as presented in the table below are prepared. Each of the ocular skin care base compositions may be used alone for the conditioning and moisturizing of the skin, or alternatively as the basis for the addition of cosmetic additives such as eye shadow or eyeliner pigments and other ingredients are suitable for use in patients suffering from dry eye syndrome or to prevent eye irritation.

(21) TABLE-US-00005 TABLE 2 Compositions Ocular/Derm w/v % Component O P Q R S T U V W X Y Jojoba Oil 0.25 — — 0.25 0.25 — 0.1 0.1 — — — Avocado Oil — 0.25 — 0.25 — 0.25 0.1 0.1 0.1 0.1 0.1 Natural Oils: — — 0.25 0.25 0.1 — 0.1 0.1 — — — Argan or Oleuropein *Simulgel ® 0.5 0.5 0.5 1.0 1.0 0.5 0.25 0.25 or *Carbopol ® 980 Polysorbate ® 80 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 Glycerin 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 *Pemulen ® 0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.01 — — — *HPMC 0.1 0.1 — — 0.25 0.25 — — 0.1 0.25 — *CMC — — — — — — 0.25 0.25 — — — PEG 400 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 — — 0.5 NaOH/HCl Adjust pH to 7.3 (spec. 7.2-7.4) Boric Acid 0.20 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 Na Borate 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 0.4 Decahydrate BAK 0.005 0.005 0.005 0.010 0.005 0.005 0.01 — 0.010 0.010 0.010 Na Chlorite — — — — — — — 0.01 — — — Tonicity 0.68 0.68 0.68 0.68 0.68 0.68 0.68 0.68 0.68 0.68 0.68 NaCl (or q.s. ad 280 to 320 mOmol NaOH/HCl Adjust pH to 7.3 (spec. 7.2-7.4) Purified q.s. ad 100 water (or WFI) Viscosity 3-50 cP (q.s. HPMC/CMC/Carbopol ® 980, where necessary)

(22) In this example Simulgel® (a family of acrylate polymers) preparations contain Polysorbate® 80. If Sumulgel® is used, additional Polysorbate® 80 should only be added if and as necessary to reach the final concentration of 0.25% (w/v). Additionally, in these examples, the thickeners Simulgel® or Carbopol®, Pemulen®, HPMC, CMC (carboxymethyl cellulose) should be adjusted in the respective proportions to each other given here to reach the desired viscosity.

(23) Example 4

(24) In order to determine suitable formulation parameters, three topical ocular formulations are made to have the following final compositions:

(25) TABLE-US-00006 TABLE 3 A B C D E F Component % (w/v) % (w/v) % (w/v) % (w/v) % (w/v) % (w/v) Avocado Oil 0.100 0.300 0.500 Jojoba Oil 0.100 0.300 0.500 Glycerin 1.00 1.00 1.00 1.00 1.00 1.00 Polysorbate ® 0.050 0.075 0.100 0.050 0.075 0.100 80 Pemulen ® 0.100 0.200 0.300 0.100 0.200 0.300 TR-2 NF Boric Acid 0.600 0.600 0.600 0.600 0.600 0.600 BAK 0.01 0.01 0.01 0.01 0.01 0.01 EDTA 0.100 0.100 0.100 0.100 0.100 0.100 0.1N NaOH To pH To pH To pH To pH To pH To pH 7.4 7.4 7.4 7.4 7.4 7.4 Water QS QS QS QS QS QS

(26) Formulations are made as follows: 1.00 g of glycerin was added to 80 g of water at room temperature and mixed in a beaker with a magnetic stir bar. Pemulen® is added (Formulations A and D: 100 mg; Formulations B and E: 200 mg; Formulations C and F: 300 mg) while continuing to mix.

(27) Polysorbate® 80 is added (Formulations A and D: 50 mg; Formulations B and E: 75 mg; Formulations C and F: 100 mg) while continuing to mix with heating for 15 minutes, then cooling. Avocado oil is added to Formulations A (100 mg), B (300 mg) and C (500 mg) and jojoba oil to Formulations D (100 mg), E (300 mg) and F (500 mg) while continuing to mix.

(28) 20 μl of a 50% (w/v) BAK solution is added with mixing, followed by 100 mg of disodium EDTA while continuing to mix. 0.1 N NaOH is added to bring the pH of the formulation to 7.4±0.3. Finally, water is then added to bring to total volume to 100 ml.

(29) Formulations B, C, E and F are found to be quite viscous, forming a non-pourable gel or paste with air bubbles entrapped within. Formulations A and D were light grey opaque viscous liquids.

(30) Example 5

(31) The high viscosity of Formulations A-F of Example 4 is surprising, particularly given the low Pemulen® concentrations; a new set of formulations containing lower amounts of Pemulen® and varying the order of addition of the components is made. Additionally, mixing is done using an IKA overhead mixer rather than by using magnetic stir plates and stir bars.

(32) Three formulations (G, G1 and H) are made using previous formulations A and D as starting points. Formulations G and G1 contain avocado oil and other ingredients in identical amounts, but differ in the order of addition of Pemulen®. Formulation H contains jojoba oil.

(33) TABLE-US-00007 TABLE 4 G G1 H Component % (w/v) % (w/v) % (w/v) Avocado Oil 0.100 0.100 Jojoba Oil 0.1 Glycerin 1.00 1.00 1.00 Polysorbate ® 80 0.05 0.05 0.05 Pemulen ® TR-2 NF 0.01 0.01 0.01 Boric Acid 0.60 0.60 0.60 BAK 0.01 0.01 0.01 EDTA 0.10 0.10 0.10 0.1N NaOH To pH 7.4 To pH 7.4 To pH 7.4 Water QS QS QS

(34) All formulations are initiated with 800 g of water in a beaker. The IKA mixer shaft and impeller is inserted into the samples and the mixing speed adjusted to 375 rpm (sufficient to draw floating material below the surface without splashing, while minimizing the amount of air drawn into the mixture).

(35) For Formulation G, the order of ingredients is: glycerin, Polysorbate® 80, avocado oil, boric acid, BAK, EDTA and 1 N NaOH to pH 7.4; all ingredients are added with mixing. Pemulen® is then added (10 ml of a 1 mg/ml solution in water). Water is then added to a final volume of 1000 ml.

(36) Formulation G1 is prepared in the same manner as Formulation G1, except Pemulen® is added following the addition of EDTA; the pH of the mixture is then adjusted with 1 N NaOH to pH 7.2 and brought to volume (1000 ml) with water.

(37) Formulation H is prepared in the same manner as Formulation G, except that jojoba oil is substituted for avocado oil.

(38) Immediately upon mixing Formulation G 1 appears to be the most uniform dispersion, lacking observable undissolved particles or solids as seen in both Formulations G and H. Formulation G1 has a viscosity of 1.1 cP, a surface tension of 31 dynes/cm and a percent transmittance at 580 nm of 4.4.

(39) The samples are divided into aliquots and incubated at 25° C. and 40° C. for 2 weeks, and observed at time 0, one week and 2 weeks. pH, osmolality and viscosity remain unchanged in all samples at both temperatures.

(40) Example 6

(41) Formulation G1 is accessed as the superior candidate artificial tear formulation in Example 5 with respect to appearance and viscosity. Two further formulations, G2 and I, are made based upon the results of Example 5; these formulations are made using avocado oil to preserve experimental rigor and congruency with Example 5; however, Applicants believe that similar results can be obtained using other oils with little or no additional experimentation. As in Example 5, mixing is done using an IKA overhead mixer rather than by using magnetic stir plates and stir bars.

(42) Formulation G2 is made in a 1 liter beaker ((“aqueous phase” Beaker A); 700 g of water are added. Boric acid and EDTA are added with mixing at 348 rpm; the pH of the mixture is then adjusted to pH 7.4 with 1 N NaOH.

(43) In a separate beaker (“oil phase” Beaker B) 500 mg of Polysorbate 80 is added to 100 g water and mixed until dissolved. 10 mg of Pemulen® is added while mixing at 348 rpm; when the Pemulen® is dissolved, 200 μl of a 50% (w) BAK solution in water is added while mixing, followed by 10 g glycerin and 1 g of avocado oil.

(44) The Contents of Beaker B are added to Beaker A while mixing at 380 rpm, and mixing continued overnight at room temperature. The pH was measured and 1 N NaOH added to adjust pH to 7.37, then the mixture was then transferred to a volumetric flask and water added to 1 liter.

(45) Formulation I is made as follows:

(46) A 1 mg/g Pemulen solution is made in water. About 80 g water is added to a beaker and 100 mg Pemulen is added and mixed using a magnetic stir bar until dissolved, then brought to 100 g with water.

(47) In a separate beaker about 25 g of water is given 500 mg Polysorbate® 80 and mixed with a stirbar so as not to incorporate air into the solution.

(48) 10 g of the Pemulen® solution is transferred to a small beaker with a stirbar, and the solution stirred while adding 250 μl (250 mg) of 18% NaOH. The Pemulen® is added to the NaOH at this stage in an attempt to cause some limited hydrolysis of the Pemulen® in order to reduce the viscosity of the solution somewhat before incorporation into the oil phase. A homogeneous mixture was not obtained at this stage without mixing. The solution was then mixed with heat for 90 minutes. A solution was maintained at about 40° C. One g of avocado oil was gently warmed to about 30° C., then added to the Pemulen® solution with mixing. Mixing is continued until a smooth homogeneous solution is formed. The temperature is maintained at 25° C.-30° C.

(49) A boric acid buffer is prepared by adding 800 g of water to a 1 liter beaker, then the following ingredients were added in sequence: 1 g glycerin, 6 g boric acid, 1 g EDTA, 1 N NaOH to adjust pH to 7.39. The entire contents of the Polysorbate® solution is then added, with mixing. The warm Pemulen®/oil mixture is then added to the buffer solution under moderate agitation, and the beaker rinsed with the buffer solution. Finally, 100 mg of BAK is added from a 50% BAK stock solution, and the final pH determined to be 7.59. The final concentrations of ingredients are as set forth in Table 5.

(50) TABLE-US-00008 TABLE 5 Form. G-2 Form. I Ingredient (% w/v) (% w/v) Avocado Oil 0.1 0.1 Glycerin 1 1 Polysorbate 80 0.05 0.05 Pemulen TR-2 NF 0.01 0.01 Boric acid 0.6 0.6 BAK 0.01 0.01 EDTA, disodium, dihydrate 0.1 0.1 NAOH — 0.0045 1N NaOH To pH 7.4 To pH 7.4 Water QS QS

(51) The appearance of Formulation G2 and I is similar. Both are light grey cloudy solutions having undissolved white particles. Of the two formulations, Formulation I contains smaller particles, while Formulation G2 contains both large and small particles.

(52) Example 7

(53) It is assessed that the results obtained with Formulations G2 and I indicate that a reduction in BAK concentration may be possible, and may assist the formulation stability. The order of addition of components will also be modified by making a stock solution of Pemulen® in borate buffer to add to the other ingredients, and the components will be mixed using a Silverson high speed mixer with an emulsion screen to aid in the emulsification process.

(54) Six liters of 0.6% (w) borate buffer are made as follows. 4.8 liters of water is given 36 g boric acid while stirring, and the pH adjusted to approximately 7.3 using 1 N NaOH. The buffer is then brought to 6 liters with additional water.

(55) Preparation of Formulation

(56) A 4 liter beaker is given 1.6 g of the 0.6% (w) borate buffer and mixed with 20 g glycerin using a magnetic stir bar. 1 g of Polysorbate® 80 is added with continued mixing. 2 g of disodium EDTA dihydrate is added with mixing. When all components are visually dissolved, the magnetic stirrer is taken away, and the Silverson mixer's emulsion mixing screen is inserted into the solution. The speed of the Silverson mixer is adjusted so as to draw floating material under the surface without splashing, and to minimize air being drawn into the water.

(57) Two g of avocado oil is then added with mixing. A Pemulen® solution (0.02 g/g) is made using 400 g of the 0.6% (w) borate buffer to dissolve 10 g of Pemulen®, then the solution brought to 500 g using e 0.6% (w) borate buffer. Ten g of the 0.02% (W) Pemulen® solution is added to the mixture of the other ingredients with mixing.

(58) 0.2 ml of a 50% (w) BAK solution is added to the mixture, yielding a final BAK concentration of 0.005% (w). The mixture is then brought to 2 liters using the 0.6% (w) borate buffer.

(59) Preparation of Formulation K

(60) Formulation K is prepared in the same manner as Formulation J, except that 30 g of the 0.02% (w) Pemulen® borate buffer solution is added to the mixture of water, glycerin, EDTA Polysorbate® 80 and avocado oil, with mixing, as described with respect to Formulation J. 0.2 ml of a 50% (w) BAK solution is added to this mixture, yielding a final BAK concentration of 0.005% (w). The mixture is then brought to 2 liters using the 0.6% (w) borate buffer.

(61) Preparation of Formulation L

(62) Formulation L is prepared in the same manner as Sample J, except that 50 g of the 0.02% (w) Pemulen® borate buffer solution is added to the mixture of water, glycerin, EDTA Polysorbate® 80 and avocado oil, with mixing, as described with respect to Formulation J. 0.2 ml of a 50% (w/v) BAK solution is then added to this mixture, yielding a final BAK concentration of 0.005% (w). The mixture is brought to 2 liters using the 0.6% (w) borate buffer.

(63) The final concentrations of ingredients are as set forth in Table 6.

(64) TABLE-US-00009 TABLE 6 Form. J Form. K Form. L Ingredient (% w/v) (% w/v) (% w/v) Avocado Oil 0.1 0.1 0.1 Glycerin 1 1 1 Polysorbate 80 0.05 0.05 0.05 Pemulen TR-2 NF 0.01 0.03 0.05 Boric acid 0.6 0.6 0.6 BAK 0.005 0.005 0.005 EDTA, disodium, 0.1 0.1 0.1 dihydrate 1N NaOH To pH 7.4 To pH 7.4 To pH 7.4 Water QS QS QS

(65) These formulations are then tested for stability at time 0 and after one week and two weeks at 25° C. and 40° C.

(66) Example 8

(67) The exemplary formulations listed below in Table 7 are made and mixed substantially as set forth in Example 7:

(68) TABLE-US-00010 TABLE 7 Form. 1 Form. 2 Form. 3 Form. 4 Form. 5 Form. 6 Form. 7 Ingredient (% w/v) (% w/v) (% w/v) (% w/v) (% w/v) (% w/v) (% w/v) Menthol Oil 0.1 Eucalyptus 0.1 Oil Fennel Oil 0.1 Bergamot 0.1 Oil Sesame Oil 0.1 Peppermint 0.1 Oil Jojoba Oil 0.1 Glycerin 1 1 1 1 1 1 1 Polysorbate 0.05 0.05 0.05 0.05 0.05 0.05 0.05 80 Pemulen 0.03 0.03 0.03 0.03 0.03 0.03 0.03 TR-2 NF Boric acid 0.6 0.6 0.6 0.6 0.6 0.6 0.6 BAK 0.005 0.005 0.005 0.005 0.005 0.005 0.005 EDTA, 0.1 0.1 0.1 0.1 0.1 0.1 0.1 disodium, dihydrate 1N NaOH To pH To pH To pH To pH To pH To pH To pH 7.4 7.4 7.4 7.4 7.4 7.4 7.4 Water QS QS QS QS QS QS QS
Example 9

(69) Stock solutions of 0.04% mg/ml Pemulen™ and 8 mg/ml Hypromellose™ (hydroxypropylmethylcellulose) are prepared by incorporating the polymers into hot DI water. The stock solutions are then stored at 5° C. overnight.

(70) The oil phases of Formulation T and Formulation U are prepared by mixing the oils with hot polysorbate 80 at 55° C. to 65° C. The oil phases are then emulsified with 40 mg/ml aqueous solution of glycerin using a Silverson high shear mixer for about 1 hour at 55° C. to 65° C., to achieve a homogenous emulsion. The remaining aqueous components and the Pemulen™ and Hypromellose™ are added by mixing into the homogeneous emulsions to form Formulation T and Formulation U. Formulation T, which contains avocado oil as the sole oil, is a uniform opaque emulsion having a white foam on the top[surface. Formulation U, which contains avocado oil and castor oil, is a uniform translucent emulsion showing no surface foam.

(71) TABLE-US-00011 TABLE 8 Form. M Form. N Form. O Form. P Form. Q Form. R Form. T Form. U Ingredient % w/v % w/v % w/v % w/v % w/v % w/v % w/v % w/v Avocado Oil 0.1 0.1 0.1 0.1 0.05 Jojoba Oil 0.1 Castor Oil 0.1 0.1 0.1 0.05 Glycerin 1 1 1 1 1 1 1 1 Polysorbate 0.05 0.05 0.05 0.05 0.05 0.05 0.4 0.4 80 Pemulen TR- 0.01 0.03 0.05 0.05 0.002 0.002 0.01 0.01 2 NF Hypromellose 0.2 0.2 0.2 0.2 Boric acid 1.2 1.2 1.2 1.2 1.2 1.2 1.1 1.1 Sodium 0.02 0.02 0.02 0.02 perborate monohydrate BAK 0.005 0.005 0.005 0.005 0 0 EDTA, 0.1 0.1 0.1 0.1 0.1 0.1 disodium, dihydrate 1N NaOH To pH To pH To pH To pH To pH To pH To pH To pH 7.4 7.4 7.4 7.4 7.4 7.4 7.4 7.4 Water QS to QS to QS to QS to QS to QS to QS to QS to 2 L 2 L 2 L 2 L 2 L 2 L 2 L 2 L

(72) These formulations are tested for pH, osmolality, surface tension and % transmittance (clarity), and the results are summarized below.

(73) TABLE-US-00012 Test Form. M Form. N Form. O Form. P Form. Q Form. R Form. T Form. U pH 7.4 7.4 7.4 7.4 7.1 7.2 7.7 7.7 7.1 7.2 7.7 7.7 Osmolality N/A N/A N/A N/A 293 294 2.86 287 (mOsm/kg) Viscosity (cP) 1.30 1.33 1.36 1.40 4.74 4.70 4.6 4.35 % 13.5 10.3 11.3 10.3 4.2 5.9 3.8 97.9 Transmittance at 578 nm Surface 40.3 37.2 36.3 36.6 48.3 49.3 46.2 45.9 Tension

(74) Thus, not only is the clarity of Formulation U greatly increased compared to Formulation T, but there is a slight decrease in viscosity when 0.1% avocado oil is replaced in an otherwise identical Formulation U with a 0.05% avocado oil and 0.05% castor oil. Otherwise the tested physiochemical characteristics of the two formulations are similar.

(75) Additionally, the presence of castor oil (e.g., Formulation O) provides a decrease in surface tension compared to single oil formulations M, Q and R. Interestingly, adding castor oil as a second oil component (i.e. formulation N which also contained jojoba oil) similarly achieves a reduction in surface tension. Noteworthy, is that the surface tension data for formulations O (castor oil only) and N (jojoba with castor oil) achieve equivalent surface tension lowering, and suggests that the addition of castor oil may have a predominant, governing effect on surface tension whether used singly or in combinations with other oils, such as plant-based oils such as avocado oil and jojoba oil.

(76) Example 10

(77) As a model of a prospective suite of therapeutic compositions to be used with the methods of the present invention, results obtained using selected tested therapeutic compositions G-1, M, N, O, P, Q, R, T and U, were tabulated, along with the viscosity (N), surface tension (ST) and Clarity (Percent Transmittance at 580 nm) parameters determined for these compositions. As explained in detail above, patient tolerability was determined to be proportional to Clarity/N, while therapeutic healing effect was determined to be proportional to N/ST.

(78) TABLE-US-00013 Surface Clarity (Percent Formulation Viscosity Tension Transmittance (& oil type) (cP) (dynes/cm) At 580 nm) G-1 (avocado) 1.1 31 4.4 M (avocado) 1.3 40.3 13.5 N (jojoba, castor) 1.33 37.2 10.3 O (castor) 1.36 36.3 11.3 P (castor) 1.4 36.6 10.3 Q (avo) 4.74 48.3 4.2 R (avo) 4.7 49.3 5.9 T (avo) 4.6 46.5 3.8 U (avo + castor) 4.35 46.5 97

(79) Thus, among these formulations, all are low viscosity (less than about 15 cP), making all of them either Formulation A or Formulation C based on viscosity alone.

(80) Formulations G-1, N, O, and P are all of low surface tension. Thus, these Formulations fall under Matrix Formulation C based on low surface tension and low viscosity. Formulation M is on the edge of normal versus low surface tension.

(81) Formulations Q, R, T and U all have higher than normal surface tension, and would tend to fall within Matrix Formulation A based on normal surface tension and low viscosity.

(82) These formulations (G-1, M, N, O, P, Q R, T and U) may be altered further to treat patients whose symptoms and signs place their optimal therapeutic formulation within Matrix Quadrants B or D by increasing viscosity and/or decreasing surface tension (e.g., by increasing the oil concentration of the formulation). Deceased surface tension of the tear aids in the spreadability of the drop over the ocular surface, and increasing the tear breakup time.

(83) The foregoing examples are simply for the purpose of illustration of various examples incorporating elements disclosed in the present specification. To the extent that a plurality of inventions may be disclosed herein, any such invention shall be understood to have disclosed herein alone, in combination with other features or inventions disclosed herein, or lacking any feature or features not explicitly disclosed as essential for that invention. For example, the inventions described in this specification can be practiced within elements of, or in combination with, other any features, elements, methods or structures described herein. Additionally, features illustrated herein as being present in a particular example are intended, in other examples of the present invention, to be explicitly lacking from the invention, or combinable with features described elsewhere in this patent application, in a manner not otherwise illustrated in this patent application or present in that particular example. The scope of the invention shall be determined solely by the language of the claims.

(84) Thus, the various descriptions of the invention provided herein illustrate presently preferred examples of the invention; however, it will be understood that the invention is not limited to the examples provided, or to the specific configurations, shapes, and relation of elements unless the claims specifically indicate otherwise. Based upon the present disclosure a person of ordinary skill in the art will immediately conceive of other alternatives to the specific examples given, such that the present disclosure will be understood to provide a full written description of each of such alternatives as if each had been specifically described.

(85) Claim terms shall be intrinsically defined not only by a specific definition in the specification, but also with reference to the Figures as understood by a person of ordinary skill in the art in light of the present disclosure.

(86) Every publication and patent document cited herein is each hereby individually incorporated by reference in its entirety for all purposes to the same extent as if each were individually denoted.