CA2102110A1 - Verapamil hci formulation and other ophthalmic solutions with buffer system for ocular administration - Google Patents
Verapamil hci formulation and other ophthalmic solutions with buffer system for ocular administrationInfo
- Publication number
- CA2102110A1 CA2102110A1 CA 2102110 CA2102110A CA2102110A1 CA 2102110 A1 CA2102110 A1 CA 2102110A1 CA 2102110 CA2102110 CA 2102110 CA 2102110 A CA2102110 A CA 2102110A CA 2102110 A1 CA2102110 A1 CA 2102110A1
- Authority
- CA
- Canada
- Prior art keywords
- composition
- buffers
- eye
- vehicle
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Ophthalmology & Optometry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
An aqueous ophthalmic solution is disclosed in which one or more acive ingredients in ionized form are gradually brought to undissociated, free base form by lacrimal solution acting against the affect of a plurality of buffers. The affect of each buffer is overcome sequentially by the lacrimal fluid. A preferred formulation includes verapamil HCl as the active ingredient in ionized form and includes as buffers: boric acid at 2.8 %, disodium edetate at 0.18 %, dextrose at 0.3 %, and polyvinylpyrrolidone at 2.0 %.
Description
2 ~
~~ 93/18764 Pcr/us93/o2~49 _~
~L~
The inventlon relates g~nerally to ophthalmic . compositions containing an active ingxedient.
Ophthalmic solutions are primarily aqueous-based pharmaceutic:als designed for topical application to the ex~ernal sur~zlce of 'che eye. They are indicated for a variety of pa~hological ~onditions in addition to being used as diagnostic aids to allow ~risualization of external ocular " ~ struc~ures and abnormalities not r~adily apparent to casual observa~ion ~y eye-care practitioners.
Consequ~n~ly, ac:tive ingredients of ocular solutions can include anesthetics, mydriatics t ag~nts t:hat ~ilate the pupil), miotic:s ~agents that constrie:t the pupil), anti-infec~ives, diagrlostics (su~:h as dyes to risualiz~ nonviable, ocular surface areas as well as other surface abno~nalities), astringents, demulcents and lubric:ants for temporary relief of ocular discomfort, as wel~ as anti-inflammatorr agents and other ingredients designed to elicit specific phaxmacological effects.
The basic produc~-relat~d requirements for an acceptable ophthalmic solution are sterility, clarity and ~reed~m from particula~es large enough to cause irritation and/or ocular damage. AdditioAally, the aqueous vehicle of the ophthalmic product should provide ~n nvironment that pro~otes ~tability for the aGtive ingredient~s)O Furthermore, the resultant opht~almic solution (a~tive and inactive inyredients) ~ould not be significantly unc~mfDrtable upon application to the eye. ~n uncomfortable ocular solutlon has two major disadvantages. Fir5t, it does not promote patient compliance when used outside the professional setting, thereby WO 93/1~764 2 1~3,~ a 2 PCT/US931025 jeopardizing the outcome of the therapeutic regimen. Second, an unc~mfortable ophthalmic solution causes irritation to the eye, albei~ tran5itory, WhiCh triggers the protective response of eXCessive tearingO Overt ~earing in response to ocular irritation is designed to wash oUt what the body perceives as ocular irritants. Unfortunately, if the ophthalmic medication is perceived as an irritant, its dwell time on the eye is reduced by the tearing, thereby compromising its desired ef~e~t.
Since one mediator of comfort is pH, emphasis has traditionally been placed on ~u~ering ocular s~lutions to specific pH ranges ~o provid~ ~aximum c~mfort and ~reatest ser~iceability o~ ~he s~lution. The pH of normal tear (lacrimal) fluid is approximately 7O2-7.~ wit~ variations being associated with different pathologies. ~ significantly uncomfortable condition occurs when pH exceeds 8 or.is under s. Thus, it has long been maintained that if eye solutions can be adjusted to pH ranges that approxi~ate those of normal tears, the resulting solution will be less irritating upon use. Disoomfort of ocular soluti~ns, when it doPs occur, is typically related to properties of the active ingredien~(s). Certain che~icals, as well as certain chemical gro~ps, are generally irritating upon ocular instillation.
However, in some situations a pH range outside the "comfort zone" of 6.~-7.2 is needed to insure stability and, conse~uently, ~he therapeukic effect of the active ingredient(s) in the formulation. Other active chemicals stable in the pH comfort zone can still be irritating as a result of their dissociation properties and profiles. In total, the number of ophthalmics that are uncomfcrtable upon instillation i5 si~nificant. They co~prise the bulk of those used in the professional setting, especially mydriatics and anesthetics. Additionally, patient orientated, long-term use drugs such as pilocarpine HCl or pilocarpine nitrate is also uncomfortable.
WO93118764 3 ~,~,s ~ PCl'/US931025q!9 Many opht~almic formulations, therefore, represeslt a compromise between two seemingly c:ften-at~odds re~uirements;
namely, in~redient stability and patient comfort.
Histc)rically, this compromise has cerltered around adjusting the p~ of particular formulation It:o ~ry an~ mee~ ~hs co~ufort needs of the patient as well as the s~ability requirements of the in~redientts) in the formulation. By necessity and practicality, considerations of com:Eort have always had lesser importance.
A review of the dissociati~n pr~files of traditionally uncomfor~able ocular medi~ations serves ~o demonstrate why their physiological and therape~tic acti~ity causes ocular discomfor~. Ophthalmic medications are physiologically and therapeutically active in their undissociated (free base) state. Generally, however, their diss~ciated ~ionized) forms ~- (or salts) are used in formulating ophthalmic products since ~hey are the most soluble. Examples of ophthalmic ~edications tha~ are t~erapeutically active in their ~dissociated form but formulated as salts, are se~ forth in .able l.
WO 93/18764 4 PC~/US93/02549 2 ~ Ta~le 1 Antihist~mines Mvdriat~s antazoline phosphate atropine sulfate naphazoline phosphate cyclopentolate hydrochloride pyrilamine maleate homatre)pine hydrobromide tetrahydrozoline hydrochloride p h e n y 1 e p h r i n e hydrochloride scopolamine hydrobromide Anesthetics Anti-In~lammatories benoxinate hydrochloride proparac:aine hydrochloride cromolyn sodium tetracaine hydroc:hloride dexamethasorle sodium phosphate prednisolone sodium phosphate Miotics demecarium bromide echot~iophate iodide gentamicin sulfate pilo::arpine hydrochloride neomyc:in sulfate pilocarpine nitrates polymyxim B sulfate sulfacetamide sodium Other timolol maleate betaxolol hydrochloride verapamil hydrochloride Upon applica~ion to the exterior eye surface, these salts are "hydrolyzed," resulting in conversion to the free base form and accompanying anion or cation~ The free base is absorbed through the eye and ultimately is responsible for the physiologic activity of the drug. It i5 the absorption of free base drug that is recognized as th~ cause of ~5 di~:comfort to the eye. Hydrolytic cleavage of the medication salt occurs because of the eye's remar)cable buffering capacity to maintain the surface pH generally between 7.2-7.4. T~e further away the pH of the applied ~cular product is from this physiologic ocular pH range, the more WO g3/18764 ~'''J~ L ~
PCl /US93/0~549 rapid and irltensi~re will be the hydrolytic activity wit~ the potential for accompanying acute, intensive discomfor~. ~he ionized ocular product may be stable in bu~fer as stored.
However, once the buf fer capacity of the drug vehicle is S "broken," the ionized form is ~ins~antaneously~' converted to ~he undissociated (fxee base) form. C~nsequently, more intense, acute dis~om~ort is realized from the use of traditional, uncompromising buffers.
Pxevious ocular mPdication ~Q~icles have attempted to lo address the uncomfortable conversion of dissociated medication to the free base by incorporating uncompro~ising chemical buffers designed t~ hold the pH of the ocular surface to that of the product for as long as possible. In cases where the pH of the product differs markedly from t~at of ~he eye, such buffsrs only act to increase the discomfort of the product by eliciting an overt physiological buffering response by ocular fluids released from the lacrimal gland as schematically illustra~ed in Fig. 1.
Recently, it has been shown that certain calcium channel blocking agents, especially verapamil, are capable of lowering elevated intraocular pressure when admi~istered topically to the hypertensive eye in solution in a ~uitable ophthalmic vehicle (~belson, U.S. Pat. No. 4,9~1,871, hereby incorporated ~y reference herein~. However, in practice, it has been difficult to obtain an ophthalmic v~hicle for verapamil ~hat will ensure patient compliance.
WO 93/18764 ~102~ l ~ 6 PCT/USg3/O~s4g Verapamil represents the classic ophthalmi~ medicatior~
stable in salt form (e.g., as verapamil HCl) in a pH
environment below that of ocular fluids. In order to maintain a reasonable shelf life, verapamil HCl ophthalmic solution should prefer~bly be maintain~d at a pH range of 5.0-5.5. ~owever, without a suitable buffering vehicle, application of verapamil HCl in shelf-stable form to the ocular surface, which is at the physiologic pH of the tearfilm (pH 7.0), results in a degrse of stinging that is intolerable for patient comp~iance.
WC~ 93/1 8764 ~, 1 J . 1 ~ 3 PCI`/US93~02549 SUMMARY OF ~ ;~YE~TlON
In broad scope, the present in~rentiorl is an ophthalmic composition for topical application to t:~e external surface of the eye, which comprises an aCtive ingredient for ef fecting a pharmacological change in the eye or as a diagnostic aid in visualizislg ocular structures. The ac:tive ingredient is applied to the eye in the form of a stable, ionized salt at a pH tha'~ is low relative ~o the pH of lacrimal fluid. The ~ctiv e in~redient is active in its undissociate~ form as a free base at a pH substantially higher than t~at in its dissociated form as an ioniz~d salt.
~, Als~ present are a plurality of buffers i~ amounts sufficient to arrest the increase in pH of the active ingredient as it changes from a salt t~ a free base in the presence of the la~rimal fluid. The buffers are differentiated from each other in their buffering capabilit:y 50 that conversion of the ac~ive ingredient from dissociated ~o free base form is moderated and sustained by successive neutralization of.
di~feren~ buffers. This gradual formation of free base imparts to the patien~ a comfort significantly greater ~han that present when only a single buffer is used and the change in pH as t~e active ingredient chan~es from dissociated to free base form is more rapid.
More specifically, it is contemplated that the invention may use a plurality of buffers, e.g., three, four, five or more. Such buffers will be of different buffering capabilities and, if desirable, the same total amounts. In WO 93/18764 PCr/US93/02~49 2 L~ 8 this way the pH of the co~position will advance in stages as the buffering capability of each buffer is overcome by the lacrimal ~luid and the pH of the comp~sition is raised toward that of the tears. Even more specifically, it is contempla~ed that a plurali~y of buffers including boric acid, disodium edetate, and polyvinylpyrrolidone (PV~) be used, t~e edeta~e ~eing the weakest and the boric acid the strongest of the weakly dissociated acids to be overcome.
Where four buffers are used, dex~ro~;~ may b~ the four~h; it lQ is still weaker than the edetate and will be the ~irst to be broken by the tears of the u5er.
In another ~spect, the invention features an ophthalmic composition for topical applica~ion to the external surface of the eye comprising verapamil a5 an acti~e ingr~dient, in the form of a stable, dissociat~d salt (verapa~il HCl~ at a p~ that is low compared to the pH of lacrimal fluid. The ophthalmic composition also i.ncludes a buffer syst~m comprising a plurality of buff~r,s in amounts sufficient to eontrol the increase in p~ of the acti~e ingredient as it changes from a salt to a free base in the presence of th.e lacrimal fluid. The buffers are differentiated ~r~m each other in their buffering capability so that conver~ion of the active ingredient from dissociated to free l~asP f~rm is modera~ed and sustained by succ:essive neutralization of different buffers. This gradual ~ormation o~ free base imparts to the patient a comfort si~nificantly greater than that present when only a single buffer is used and the change WO 93/ 1 8764 L D ~ $ `~ O PCT/US93~02~49 in pH as the active ingredient changes from dissociated to free base f~rm is more rapid.
Preferably, the buffers in t~e buff~ring system are boric acid at a concentration of 0.5-3.0%, most preferably 2.8%; disodium edetate at a concentration of 0.08-0.5%, most preferably 0.18%; dextrose. at a ~oncentration of 0.1-5.0%, most preferably 0.3~: and polyvinylpyrrolidone at a c~ncentration of 1.0-4.0%, most preferably 2.0~
concentrations are by weight~ The composition may also inclu~e a preservative, most preferably benzalkonium chloride.
The ophthalmic co~position of the invention serves to moderate the physiological buffering response of the lacrimal fluids. .Unlike traditional buffer chemicals which only momentarily adjust the pH of the. Dculal^ surface to that of the product then instantly "break'l when overpowered by ocular fluids, the compQsition of t~e present inYention provides a sustained, controlled, degrading, "trenched" buf~ering resp~nse. Ins~ead of attempting to hold a predetermined, product oriented pH environment on the ocular surface, it allows adjustment of the ocular pH by lacrimal fluids over a period of up to approximately 60 second~. For example, it is contemplated that a composition stored at a pH of about 3 would reach a pH greater t~an 6.5 after about one minute 2S following application to the eye and would have a p~ less than 6.5, even less than 6.0 or 5.5, 30 seco~ds after installation. This trenched pH chanqe allows sustained, WO 93/1~764 ~ 1 ~ 2 1 ~ o PCI'/US93102~;49 rather than immediate, conversion of the dissociated medicati~n to the undissociated form~
By avoiding instantaneoUs Conversion o~i all ~he ionized medication, ~he composition allows for gradual c:onversion of S the dissociated forsn to th?~' undissociated, absorbable form of the active agent. The slower conversion resul~s in lower concentration of undissocia~ed ærug on ~h~ eye at any one time, thereby lessening or avoiding the discomfort associated with the undissocia~ed drug. Since ~he eye perceives less to no irritation, the tearing response is lessened, thereby allowing a longer dwell time of the medication on the ocular surface ~ ~ .
Other features and advantages OI the invesltion will be apparent ~rom the following descrip~ion of the preferred embodimen~ thereof and from the clai~s ~aken in conjunction with the accompanying drawings iIl WhiCho Fig. 1 ~hows a tradition~l buffer drug discomfort rela~ionship: and Fig. 2 shows a drug discomfort relationship in the buffer sys~em of the invention.
The Lacrimal Aotivated Buffer System (LABS) of the invention is designed t~ control (by ~oderating) ~he physiological bu~fering response of the lacrimal fluids to 2s the pH o~ stored ophthalmic solutions containing certain active ingredients. Unlike traditional buffered compositions WO 93~18764 11 ~'';'3 :L ~ P~/US93~025.a9 which onlv momentarily adjust the pH of the ocular surface to that of the product and then instantly "break" when overpc:wered by ocular fluids, LA33S is formulated to provide a sustained, controlled, degrading "tren~hed" buffering response. Instead of attempting to hold a predetermined product oriented pH environment on the ocular surface, LABS
allows continual adjustment of the ~cular pH by lacrimal fluids over a period of time which can last up to approximately 60 seconds. Consequently, this trenched pH
change allows sustained, rather t~an immediate, conversion of the dissociated (ionized~ form of the active insredient to its un~issociated (nonionized) form. By avoiding instan~aneous conversion of all the ionized product, e.g., verapamil HCl, the me~ered change of the L~BS induced pH
environment on the eye allows for gradual conversion of the dissociated form to its undissociated, absorbable, therapeutically active form (e-g-, verapamil) as schematically illustrated in Fig. 2. This slower conversi~n results in a lower concentration of undissociated drug on the eye at any one time, thereby lesseniny or avoiding the discomfor~ associated with its presence. Since the eye perceives less-to--no irritation, the tearing re5ponse is lessened or negated, thereby allowing a lsnger resident time for the undissociated drug ~n the ocular surface.
~he controlled shift in the dissociation/undissociation equilibrium reaction of the active ingredient is mediated by a formulation that utilizes a select number and variety of ., WO 93/1~764 ~ , L ~ 12 PCT/US93/02~49 weak, acidic chemlcals that consequently are only mildly dissociated in aqueous media. Mos~ o~en, these weakly dissociated, acidic chemicals and their preferred concentration ranges include, but are not limited to: :
Boric Acid, USP grade (0.5-3.G%) Disodium ~detate, USP grade ~0.08-0.5%) Dextrose, USP grade (0.l 5.0%) Polyvinylpyrrolidone (PVP), USP grade (~.0-4.0%) All the aforelisted ingredients are recognized and acceptable for ocular pharmaceutical formulations and, ~;:
indeed, are used in many available eye pxeparations. Their inclusion, however, is for ~ther reasons not rela~ed to their use as explained in this application. For example, boric acid has an~imicr~bial and uncompromisiny pH adjusting .
properties when used alone, disodium edetate and dextrose can chemically stabilize certain op~thalmic active ingredients, and, additionally, disodium edet;~te exhibits antlmicrobial activity. PVP is typically included in ~ormulations to increase viscosi~y and/or serve as a suspending agent.
While c~ncentrations outside t~e preferred ranges are not ineffectual for influencing dissociation rates of some -active, ophthalmic ingredients, these are the concentr~tions preferred at present. It is preferre~ that all four of the listed buffering compounds be used t~ether; nevertheless, use o~ at leas~ two of the buffering compounds in a specific formulation is consistent with providing controlled dissociation of certain active ingredients.
wo93/18764 2 ~ ~ ?~ PCT/US93/02549 The number of buffers and their concentrations is generally related to the discomfort imparted by a specific active ingredient. Additionally, it will be recognized that other organic and/or inorganic chemicals can be used in place of some or all of the common buff~rs listed. These buffers enjoy the qreatest use largely because they are recognized as safe ~or use in ophthalmic preparations. -.
Exemplarily, other weakly dissocia~ing acidic substancPs such as alginic acid, cyclamic acid, ~detate calcium ;~
disodium, gluronic acid, and sorbic acid m~y be used in proper concentrations in formulation~ according to the inven~ion. ;:
,,. ~ . .
Lik~wise, concomitant use of a strong base such as sodium hydroxide and/or stron~ acid uch as hydrochloric acid is consis~ent for inclusion into the preferred embodiments in order to brinq the formulation to ~he appropriate final pH range for optimal shelf s~ab:ility.
In addition, pharmaceutically acceptable antimicrobial preservatives can be included. Examples of compatible preservatives include, but ar~ not limited to benzalkonium chloride, edetate disodium, pheny~me~curic nitrate, silver pro~ein salts, sorbic acid, and thimerosal. It will be apparent from this list that certain agents may serve a dual func~ion as a preservative and a buf~er. The choice of preservative is contingent on the active ingredients present and profile of the buffers used.
WO 93/18764 ~ J 1 .~ U 14 PCT/US93/02~49 In the pref~rred em~odimen~ of the invention the LABS
formulation is used to act as a comfort vehicle for verapamil HCl, and the preferred concentrations of the buffering ingredients are as follGws:
Boric Acid 2.8%
Disodium Edetate 0.18 Dextrose 0.3~
PVP 2.0%
Additionally, benzalkonium chloride (BAC) is included in ~he preferred LABS formulation. BAC serves as an antimicrobial agent to maintain the sterility of ~he packaged . solution in multidose containers. If the .colution is packaged in unit-of-use (one time use containers), the BAC
is omitted from the formu}a~ion since it does not contribute to the flexi~le ~uffering proper~ies of the formulation.
The mechanism of action of t:he LABS formulation is based on the capability of its ingredi~nts to be buffered up to the phys~ologic pH range of ocular fluids concurrent wit~ the "uncomfortable" active ingredient(s). Being weakly acidic chemicals, each of the L~BS ingredients offers a different degree of weak resistance to the buffering activity of ocular fluid. The LAB~ ingredi~nt having the weakest resistance (least bufferiny properties) is neutralized irst.
Neutralization of the other buffering ingredients continues from the second weakest to the ingredient ~aving most resis~ance to pH change. Specifically, if the four common . ' :.,''', ..
, . . . ~ .... .. . ... ... . . .. .. . . . . .. . .. .. ..
WO 93/1X764 2 ~ ~s'l:lD PCT/US93/02549 buffers of the preferred embodiment are present, the theoretical order of neutralization of ~his formulation is;
dextrose ~ disodium edetate--~PVP~ ~ ~oric acid (weakest =~ strongest) based on their ln vitro buffering capacities.
Therefore, as each L~BS ingredient is neutralized (~uffered to approximately pH 7.0) the pH of the ocular fluids gradually rises. As ~he pH rises (or as acidity is reduced) more of the dissociated product, e.g., verapamil lG HCl, is converted, hydrolytically, to undissociated product, e.g., absorbable verapamil free base. ~ecause this conversion is moderated and sustained by successive neutralization of LABS ingredients (the trench bufer phenomenon), the ocular discomfort ass~ciated with l~ instantaneous, total conversion to free base is largely reduced or negated. The average concentration of free base gradually rises as the ocular surface pH rises (due to neutralization of LABS ingredients) until it reaches maximum concentration and then diminishes. It follows, ~herefore, that the plurality of buffers must be qualitatively and quantitatively cus~om tailored to the dissociation profile of the ac~ive ingredients present in a cpecific formulation.
Three factors are simultaneously in play that help avoid overt free base concentration on the ocular surface l) as the free base forms, it is absorbed away from the ocular sur~ace into interior eye tissue t 2 ~
2) the tearfilm activity constantly removes drua product from the ocular surface, and 3) the free base is formed gradually.
The first two phenomena are common to instillation of all eye drops; however, it is the third phenomenon that distinguish~s the activity of LABS from other buffer compositions used to impart comfort to ocular preparations.
- Therefore, the buffering system of the invention can be customized to impart comfort to a specific ophthalmic 10 ~ formulation by adjusting the concentration of each buffer and altering the number of buffers. As a result, an almost infinite number of "comfort patterns" can be devised to effect the controlled conversion of dissociated drug to undissociated drug. The degree of comfort required is a function of the dissociation profile of the active ingredients ~Jith respect to characteristics and degree of free base formed in an environment approximating or somewhat less than pH 7. Stability of a vast majority of active ophthalmic ingredients i5 enhanced in this pH range. So, the pharmaceutical product can be adjusted to a pH range where long-term stability is ensured even if it is significantl~
below the pH of the eye. Consequently, the requirements of stability and comfort can both be addressed without compromising either one.
2~ In another embodiment the ophthalmic solution of the invention may be regarded as an aqueous solution of a medicament in an aqueous ophthalmic vehicle containing an , ,~ .. , .. ., .. . ., ~ ., ., .. ,. ., .. .... , .. ,. ., .. .. . .. , .. .. , .. , .. . . .. ., .. ~ , 4 PCT/U~93~0~549 amount of an ophthalmologically acceptable acidifying reagent sufficient to maintain the solution at an acidic pH in the range of 4. 5-5 . 5 during storage, and an amount of an ophthalmologically acceptable buffer having a pH range between the pH of the solution and the normal pH of the mammalian eye sufficient to cause the pH of the ocular fluid to return gradually to its normal value after a dose of the ophthalmic vehicle i5 instilled into the eye.
The ophthalmic vehicle of the invention may be used to lo '~ formulate medicaments to be administered topically to the eye, when the active ingredients have to be stored at a relatively low pH for stability, but are significantly absorbed only from solutions near physiological pH.
Consequently, the ophthalmic solution of the invention 1, will include an acidifying agent, often referred to in this art as a "buffer", which will adjust the pH of the vehicle to a range suitable for long term storage of the active ingredient, typically pH 4.5-5.5. The acidifying agent will typically be a weak acid, such as boric acid, sorbic acid or the li~.e.
The ophthalmic solution of the invention will include one or more intermediate buffers, i.e., compounds having ~uffering capacity at a pH between the acidic pH to which the vehicle is adjusted for long-term stability of the active 2~ ingredient and the normal pH of the eye, i.e., 7.2-7.~. A
buffer solution, as is well known to those skilled in this art, is one which experiences relatively little change in pH
WO g3/1~76~ PCT/U~93/02549 2 ~ 18 when an acid or base is added thereto. Buffer solutions typically comprise an aqueous solution of a substance which can react with added acid or base to prevent a rapid change - in pH as the acid or base is added. The theory and practice of using buf~ers is well known. A sui~able buffer may be a mixture of a weak acid and its salt, i.e., a partially neutralized wea~ acid. Typically, such mixtures exhibit their ~aximum buffering capacity, i.e., their greatest resistance to change in pH with added acid or base, at a p~
o b- at which the acid is about half neutralized. However, buffers may include materials e.g., water-soluble polymers or organic compounds, for which the theury of their buffering capacity is not so easily expressed mathematically.
Nevertheless, such materials can be investigated experimentally and characterized as to their resistance to change in pH when an acid or base is added to an aqueous solution containing them. Thus, the skilled practitioner can readily identify suitable buffering materials for use in the compositions of this invention. For example, the practi~ioner may select a buffer mixture derived from a weak acid which will be partially neutralized at the desired buffer pH, i.e., an acid having a pKa close to the chosen buffer pH. Alternatively, the practitioner may make use of the knswn properties of water-soluble polymers such as poly(vinylpyrrolidone) or organic compounds such as dextrose.
WO 93/1876~ PCT/US93/0~49 Evidently, the practitioner may select one or more ophthalmologlcally acceptable buffering materials and adjust ~- their concentrations in the ophthalmic solution to achieve the desire~ gradual neutralization when they are instilled into the eye. In particular, a plurality of intermediate buffers may be used, each having effective buffering action at a different pH within the range from the acidic pH at -~hich the ophthalmic solution is kept to enhance its shelf life and the normal pH of the eye, i.e., in the range of 10 ~~ about ;.5 to about 7.2. In such a buffer mixture the pH will rise gradually as the eye neutralizes each buffer material n successlon.
Preferred materials usable in the ophthalmic vehicle of the invention include boric acid as an acidifying agent and, ,; ,~ ,:
as intermediate buffers, disodium eAetate, dextrose, and poly(vinylpyrrolidone)(PVP). Among such buffers, the PvP has ~ `:
been found to have significant buffer capacity at a pH:
between the original acidic pH of the vehicle, i.e., abou~
:
s~ . 5-5 . 5, and the pH of the lacrimal fluids, i.e., 7.2-7.
Si~ilarl~, the disodium edetate, which has a pKa in this ~
range, will be expected to have buffering capacity in this :~;
pH range. Dextrose, as well, can be used a buffer in the pH ;`
range slightly acidic relative to the natural pH of the -~;
lacrimal fluids.
Other ophthalmologically acceptable buffers may also be used in the vehicle of this invention, e.g., phosphate;~
buffers and citrate ~uffers, as well as other weakly WO93/187~4 PCT~VS93/02549 0 ~ -31 ~ ; 20 dissociating acidic substances such as alginic acid, cyclamic acid, edetate calcium disodium, glucuronic acid, sorbic acid and the like.
The amount of intermediate buffer incorporated into the ophthalmic vehicle of the invention should be sufficient to pr~vide enough buffering capacity to cause a relatively slow return of the precorneal lacrimal fluid to the normal physiological pH. The duration of this gradual rise in pH
to be chosen for a particular medicament will depend on the 10 ~~ particular drug used, the concentration of the drug required for therapeutic purposes, and the propensity of the drug to cause ocular discomfort. Typically a duration of about 60 seconds ~7ill provide a period long enough for substantial absorption of the drug while keeping the instantaneous concentration of the free base form small enough to minimize discomfort. However, longer or shorter durationa can be effected by adjusting the concentration of the intermedlate buffers. The choice of concentration of intermediate buffers for a given drug and therapeutic concentration thereof is a matter that can be easily determined by the skilled practitioner.
Use .~,A.
Verapamil HCl in the LABS buffer composition can be administered topically to the external surface of the eye to lowe. elevated intraocular pressure. The effective dose used WO 93/1~764 PCT/US93~025~9 2 ~ ;l D
will vary depending on the particular patient. However, a typical dose will range from about 10 micrograms to about ~ ~
1 milligram per eye per day. ~:
- ~ypically, the concentration of verapamil HCl in the buffer solution will vary from about 0.1 mg/ml to about:~
~~ 93/18764 Pcr/us93/o2~49 _~
~L~
The inventlon relates g~nerally to ophthalmic . compositions containing an active ingxedient.
Ophthalmic solutions are primarily aqueous-based pharmaceutic:als designed for topical application to the ex~ernal sur~zlce of 'che eye. They are indicated for a variety of pa~hological ~onditions in addition to being used as diagnostic aids to allow ~risualization of external ocular " ~ struc~ures and abnormalities not r~adily apparent to casual observa~ion ~y eye-care practitioners.
Consequ~n~ly, ac:tive ingredients of ocular solutions can include anesthetics, mydriatics t ag~nts t:hat ~ilate the pupil), miotic:s ~agents that constrie:t the pupil), anti-infec~ives, diagrlostics (su~:h as dyes to risualiz~ nonviable, ocular surface areas as well as other surface abno~nalities), astringents, demulcents and lubric:ants for temporary relief of ocular discomfort, as wel~ as anti-inflammatorr agents and other ingredients designed to elicit specific phaxmacological effects.
The basic produc~-relat~d requirements for an acceptable ophthalmic solution are sterility, clarity and ~reed~m from particula~es large enough to cause irritation and/or ocular damage. AdditioAally, the aqueous vehicle of the ophthalmic product should provide ~n nvironment that pro~otes ~tability for the aGtive ingredient~s)O Furthermore, the resultant opht~almic solution (a~tive and inactive inyredients) ~ould not be significantly unc~mfDrtable upon application to the eye. ~n uncomfortable ocular solutlon has two major disadvantages. Fir5t, it does not promote patient compliance when used outside the professional setting, thereby WO 93/1~764 2 1~3,~ a 2 PCT/US931025 jeopardizing the outcome of the therapeutic regimen. Second, an unc~mfortable ophthalmic solution causes irritation to the eye, albei~ tran5itory, WhiCh triggers the protective response of eXCessive tearingO Overt ~earing in response to ocular irritation is designed to wash oUt what the body perceives as ocular irritants. Unfortunately, if the ophthalmic medication is perceived as an irritant, its dwell time on the eye is reduced by the tearing, thereby compromising its desired ef~e~t.
Since one mediator of comfort is pH, emphasis has traditionally been placed on ~u~ering ocular s~lutions to specific pH ranges ~o provid~ ~aximum c~mfort and ~reatest ser~iceability o~ ~he s~lution. The pH of normal tear (lacrimal) fluid is approximately 7O2-7.~ wit~ variations being associated with different pathologies. ~ significantly uncomfortable condition occurs when pH exceeds 8 or.is under s. Thus, it has long been maintained that if eye solutions can be adjusted to pH ranges that approxi~ate those of normal tears, the resulting solution will be less irritating upon use. Disoomfort of ocular soluti~ns, when it doPs occur, is typically related to properties of the active ingredien~(s). Certain che~icals, as well as certain chemical gro~ps, are generally irritating upon ocular instillation.
However, in some situations a pH range outside the "comfort zone" of 6.~-7.2 is needed to insure stability and, conse~uently, ~he therapeukic effect of the active ingredient(s) in the formulation. Other active chemicals stable in the pH comfort zone can still be irritating as a result of their dissociation properties and profiles. In total, the number of ophthalmics that are uncomfcrtable upon instillation i5 si~nificant. They co~prise the bulk of those used in the professional setting, especially mydriatics and anesthetics. Additionally, patient orientated, long-term use drugs such as pilocarpine HCl or pilocarpine nitrate is also uncomfortable.
WO93118764 3 ~,~,s ~ PCl'/US931025q!9 Many opht~almic formulations, therefore, represeslt a compromise between two seemingly c:ften-at~odds re~uirements;
namely, in~redient stability and patient comfort.
Histc)rically, this compromise has cerltered around adjusting the p~ of particular formulation It:o ~ry an~ mee~ ~hs co~ufort needs of the patient as well as the s~ability requirements of the in~redientts) in the formulation. By necessity and practicality, considerations of com:Eort have always had lesser importance.
A review of the dissociati~n pr~files of traditionally uncomfor~able ocular medi~ations serves ~o demonstrate why their physiological and therape~tic acti~ity causes ocular discomfor~. Ophthalmic medications are physiologically and therapeutically active in their undissociated (free base) state. Generally, however, their diss~ciated ~ionized) forms ~- (or salts) are used in formulating ophthalmic products since ~hey are the most soluble. Examples of ophthalmic ~edications tha~ are t~erapeutically active in their ~dissociated form but formulated as salts, are se~ forth in .able l.
WO 93/18764 4 PC~/US93/02549 2 ~ Ta~le 1 Antihist~mines Mvdriat~s antazoline phosphate atropine sulfate naphazoline phosphate cyclopentolate hydrochloride pyrilamine maleate homatre)pine hydrobromide tetrahydrozoline hydrochloride p h e n y 1 e p h r i n e hydrochloride scopolamine hydrobromide Anesthetics Anti-In~lammatories benoxinate hydrochloride proparac:aine hydrochloride cromolyn sodium tetracaine hydroc:hloride dexamethasorle sodium phosphate prednisolone sodium phosphate Miotics demecarium bromide echot~iophate iodide gentamicin sulfate pilo::arpine hydrochloride neomyc:in sulfate pilocarpine nitrates polymyxim B sulfate sulfacetamide sodium Other timolol maleate betaxolol hydrochloride verapamil hydrochloride Upon applica~ion to the exterior eye surface, these salts are "hydrolyzed," resulting in conversion to the free base form and accompanying anion or cation~ The free base is absorbed through the eye and ultimately is responsible for the physiologic activity of the drug. It i5 the absorption of free base drug that is recognized as th~ cause of ~5 di~:comfort to the eye. Hydrolytic cleavage of the medication salt occurs because of the eye's remar)cable buffering capacity to maintain the surface pH generally between 7.2-7.4. T~e further away the pH of the applied ~cular product is from this physiologic ocular pH range, the more WO g3/18764 ~'''J~ L ~
PCl /US93/0~549 rapid and irltensi~re will be the hydrolytic activity wit~ the potential for accompanying acute, intensive discomfor~. ~he ionized ocular product may be stable in bu~fer as stored.
However, once the buf fer capacity of the drug vehicle is S "broken," the ionized form is ~ins~antaneously~' converted to ~he undissociated (fxee base) form. C~nsequently, more intense, acute dis~om~ort is realized from the use of traditional, uncompromising buffers.
Pxevious ocular mPdication ~Q~icles have attempted to lo address the uncomfortable conversion of dissociated medication to the free base by incorporating uncompro~ising chemical buffers designed t~ hold the pH of the ocular surface to that of the product for as long as possible. In cases where the pH of the product differs markedly from t~at of ~he eye, such buffsrs only act to increase the discomfort of the product by eliciting an overt physiological buffering response by ocular fluids released from the lacrimal gland as schematically illustra~ed in Fig. 1.
Recently, it has been shown that certain calcium channel blocking agents, especially verapamil, are capable of lowering elevated intraocular pressure when admi~istered topically to the hypertensive eye in solution in a ~uitable ophthalmic vehicle (~belson, U.S. Pat. No. 4,9~1,871, hereby incorporated ~y reference herein~. However, in practice, it has been difficult to obtain an ophthalmic v~hicle for verapamil ~hat will ensure patient compliance.
WO 93/18764 ~102~ l ~ 6 PCT/USg3/O~s4g Verapamil represents the classic ophthalmi~ medicatior~
stable in salt form (e.g., as verapamil HCl) in a pH
environment below that of ocular fluids. In order to maintain a reasonable shelf life, verapamil HCl ophthalmic solution should prefer~bly be maintain~d at a pH range of 5.0-5.5. ~owever, without a suitable buffering vehicle, application of verapamil HCl in shelf-stable form to the ocular surface, which is at the physiologic pH of the tearfilm (pH 7.0), results in a degrse of stinging that is intolerable for patient comp~iance.
WC~ 93/1 8764 ~, 1 J . 1 ~ 3 PCI`/US93~02549 SUMMARY OF ~ ;~YE~TlON
In broad scope, the present in~rentiorl is an ophthalmic composition for topical application to t:~e external surface of the eye, which comprises an aCtive ingredient for ef fecting a pharmacological change in the eye or as a diagnostic aid in visualizislg ocular structures. The ac:tive ingredient is applied to the eye in the form of a stable, ionized salt at a pH tha'~ is low relative ~o the pH of lacrimal fluid. The ~ctiv e in~redient is active in its undissociate~ form as a free base at a pH substantially higher than t~at in its dissociated form as an ioniz~d salt.
~, Als~ present are a plurality of buffers i~ amounts sufficient to arrest the increase in pH of the active ingredient as it changes from a salt t~ a free base in the presence of the la~rimal fluid. The buffers are differentiated from each other in their buffering capabilit:y 50 that conversion of the ac~ive ingredient from dissociated ~o free base form is moderated and sustained by successive neutralization of.
di~feren~ buffers. This gradual formation of free base imparts to the patien~ a comfort significantly greater ~han that present when only a single buffer is used and the change in pH as t~e active ingredient chan~es from dissociated to free base form is more rapid.
More specifically, it is contemplated that the invention may use a plurality of buffers, e.g., three, four, five or more. Such buffers will be of different buffering capabilities and, if desirable, the same total amounts. In WO 93/18764 PCr/US93/02~49 2 L~ 8 this way the pH of the co~position will advance in stages as the buffering capability of each buffer is overcome by the lacrimal ~luid and the pH of the comp~sition is raised toward that of the tears. Even more specifically, it is contempla~ed that a plurali~y of buffers including boric acid, disodium edetate, and polyvinylpyrrolidone (PV~) be used, t~e edeta~e ~eing the weakest and the boric acid the strongest of the weakly dissociated acids to be overcome.
Where four buffers are used, dex~ro~;~ may b~ the four~h; it lQ is still weaker than the edetate and will be the ~irst to be broken by the tears of the u5er.
In another ~spect, the invention features an ophthalmic composition for topical applica~ion to the external surface of the eye comprising verapamil a5 an acti~e ingr~dient, in the form of a stable, dissociat~d salt (verapa~il HCl~ at a p~ that is low compared to the pH of lacrimal fluid. The ophthalmic composition also i.ncludes a buffer syst~m comprising a plurality of buff~r,s in amounts sufficient to eontrol the increase in p~ of the acti~e ingredient as it changes from a salt to a free base in the presence of th.e lacrimal fluid. The buffers are differentiated ~r~m each other in their buffering capability so that conver~ion of the active ingredient from dissociated to free l~asP f~rm is modera~ed and sustained by succ:essive neutralization of different buffers. This gradual ~ormation o~ free base imparts to the patient a comfort si~nificantly greater than that present when only a single buffer is used and the change WO 93/ 1 8764 L D ~ $ `~ O PCT/US93~02~49 in pH as the active ingredient changes from dissociated to free base f~rm is more rapid.
Preferably, the buffers in t~e buff~ring system are boric acid at a concentration of 0.5-3.0%, most preferably 2.8%; disodium edetate at a concentration of 0.08-0.5%, most preferably 0.18%; dextrose. at a ~oncentration of 0.1-5.0%, most preferably 0.3~: and polyvinylpyrrolidone at a c~ncentration of 1.0-4.0%, most preferably 2.0~
concentrations are by weight~ The composition may also inclu~e a preservative, most preferably benzalkonium chloride.
The ophthalmic co~position of the invention serves to moderate the physiological buffering response of the lacrimal fluids. .Unlike traditional buffer chemicals which only momentarily adjust the pH of the. Dculal^ surface to that of the product then instantly "break'l when overpowered by ocular fluids, the compQsition of t~e present inYention provides a sustained, controlled, degrading, "trenched" buf~ering resp~nse. Ins~ead of attempting to hold a predetermined, product oriented pH environment on the ocular surface, it allows adjustment of the ocular pH by lacrimal fluids over a period of up to approximately 60 second~. For example, it is contemplated that a composition stored at a pH of about 3 would reach a pH greater t~an 6.5 after about one minute 2S following application to the eye and would have a p~ less than 6.5, even less than 6.0 or 5.5, 30 seco~ds after installation. This trenched pH chanqe allows sustained, WO 93/1~764 ~ 1 ~ 2 1 ~ o PCI'/US93102~;49 rather than immediate, conversion of the dissociated medicati~n to the undissociated form~
By avoiding instantaneoUs Conversion o~i all ~he ionized medication, ~he composition allows for gradual c:onversion of S the dissociated forsn to th?~' undissociated, absorbable form of the active agent. The slower conversion resul~s in lower concentration of undissocia~ed ærug on ~h~ eye at any one time, thereby lessening or avoiding the discomfort associated with the undissocia~ed drug. Since ~he eye perceives less to no irritation, the tearing response is lessened, thereby allowing a longer dwell time of the medication on the ocular surface ~ ~ .
Other features and advantages OI the invesltion will be apparent ~rom the following descrip~ion of the preferred embodimen~ thereof and from the clai~s ~aken in conjunction with the accompanying drawings iIl WhiCho Fig. 1 ~hows a tradition~l buffer drug discomfort rela~ionship: and Fig. 2 shows a drug discomfort relationship in the buffer sys~em of the invention.
The Lacrimal Aotivated Buffer System (LABS) of the invention is designed t~ control (by ~oderating) ~he physiological bu~fering response of the lacrimal fluids to 2s the pH o~ stored ophthalmic solutions containing certain active ingredients. Unlike traditional buffered compositions WO 93~18764 11 ~'';'3 :L ~ P~/US93~025.a9 which onlv momentarily adjust the pH of the ocular surface to that of the product and then instantly "break" when overpc:wered by ocular fluids, LA33S is formulated to provide a sustained, controlled, degrading "tren~hed" buffering response. Instead of attempting to hold a predetermined product oriented pH environment on the ocular surface, LABS
allows continual adjustment of the ~cular pH by lacrimal fluids over a period of time which can last up to approximately 60 seconds. Consequently, this trenched pH
change allows sustained, rather t~an immediate, conversion of the dissociated (ionized~ form of the active insredient to its un~issociated (nonionized) form. By avoiding instan~aneous conversion of all the ionized product, e.g., verapamil HCl, the me~ered change of the L~BS induced pH
environment on the eye allows for gradual conversion of the dissociated form to its undissociated, absorbable, therapeutically active form (e-g-, verapamil) as schematically illustrated in Fig. 2. This slower conversi~n results in a lower concentration of undissociated drug on the eye at any one time, thereby lesseniny or avoiding the discomfor~ associated with its presence. Since the eye perceives less-to--no irritation, the tearing re5ponse is lessened or negated, thereby allowing a lsnger resident time for the undissociated drug ~n the ocular surface.
~he controlled shift in the dissociation/undissociation equilibrium reaction of the active ingredient is mediated by a formulation that utilizes a select number and variety of ., WO 93/1~764 ~ , L ~ 12 PCT/US93/02~49 weak, acidic chemlcals that consequently are only mildly dissociated in aqueous media. Mos~ o~en, these weakly dissociated, acidic chemicals and their preferred concentration ranges include, but are not limited to: :
Boric Acid, USP grade (0.5-3.G%) Disodium ~detate, USP grade ~0.08-0.5%) Dextrose, USP grade (0.l 5.0%) Polyvinylpyrrolidone (PVP), USP grade (~.0-4.0%) All the aforelisted ingredients are recognized and acceptable for ocular pharmaceutical formulations and, ~;:
indeed, are used in many available eye pxeparations. Their inclusion, however, is for ~ther reasons not rela~ed to their use as explained in this application. For example, boric acid has an~imicr~bial and uncompromisiny pH adjusting .
properties when used alone, disodium edetate and dextrose can chemically stabilize certain op~thalmic active ingredients, and, additionally, disodium edet;~te exhibits antlmicrobial activity. PVP is typically included in ~ormulations to increase viscosi~y and/or serve as a suspending agent.
While c~ncentrations outside t~e preferred ranges are not ineffectual for influencing dissociation rates of some -active, ophthalmic ingredients, these are the concentr~tions preferred at present. It is preferre~ that all four of the listed buffering compounds be used t~ether; nevertheless, use o~ at leas~ two of the buffering compounds in a specific formulation is consistent with providing controlled dissociation of certain active ingredients.
wo93/18764 2 ~ ~ ?~ PCT/US93/02549 The number of buffers and their concentrations is generally related to the discomfort imparted by a specific active ingredient. Additionally, it will be recognized that other organic and/or inorganic chemicals can be used in place of some or all of the common buff~rs listed. These buffers enjoy the qreatest use largely because they are recognized as safe ~or use in ophthalmic preparations. -.
Exemplarily, other weakly dissocia~ing acidic substancPs such as alginic acid, cyclamic acid, ~detate calcium ;~
disodium, gluronic acid, and sorbic acid m~y be used in proper concentrations in formulation~ according to the inven~ion. ;:
,,. ~ . .
Lik~wise, concomitant use of a strong base such as sodium hydroxide and/or stron~ acid uch as hydrochloric acid is consis~ent for inclusion into the preferred embodiments in order to brinq the formulation to ~he appropriate final pH range for optimal shelf s~ab:ility.
In addition, pharmaceutically acceptable antimicrobial preservatives can be included. Examples of compatible preservatives include, but ar~ not limited to benzalkonium chloride, edetate disodium, pheny~me~curic nitrate, silver pro~ein salts, sorbic acid, and thimerosal. It will be apparent from this list that certain agents may serve a dual func~ion as a preservative and a buf~er. The choice of preservative is contingent on the active ingredients present and profile of the buffers used.
WO 93/18764 ~ J 1 .~ U 14 PCT/US93/02~49 In the pref~rred em~odimen~ of the invention the LABS
formulation is used to act as a comfort vehicle for verapamil HCl, and the preferred concentrations of the buffering ingredients are as follGws:
Boric Acid 2.8%
Disodium Edetate 0.18 Dextrose 0.3~
PVP 2.0%
Additionally, benzalkonium chloride (BAC) is included in ~he preferred LABS formulation. BAC serves as an antimicrobial agent to maintain the sterility of ~he packaged . solution in multidose containers. If the .colution is packaged in unit-of-use (one time use containers), the BAC
is omitted from the formu}a~ion since it does not contribute to the flexi~le ~uffering proper~ies of the formulation.
The mechanism of action of t:he LABS formulation is based on the capability of its ingredi~nts to be buffered up to the phys~ologic pH range of ocular fluids concurrent wit~ the "uncomfortable" active ingredient(s). Being weakly acidic chemicals, each of the L~BS ingredients offers a different degree of weak resistance to the buffering activity of ocular fluid. The LAB~ ingredi~nt having the weakest resistance (least bufferiny properties) is neutralized irst.
Neutralization of the other buffering ingredients continues from the second weakest to the ingredient ~aving most resis~ance to pH change. Specifically, if the four common . ' :.,''', ..
, . . . ~ .... .. . ... ... . . .. .. . . . . .. . .. .. ..
WO 93/1X764 2 ~ ~s'l:lD PCT/US93/02549 buffers of the preferred embodiment are present, the theoretical order of neutralization of ~his formulation is;
dextrose ~ disodium edetate--~PVP~ ~ ~oric acid (weakest =~ strongest) based on their ln vitro buffering capacities.
Therefore, as each L~BS ingredient is neutralized (~uffered to approximately pH 7.0) the pH of the ocular fluids gradually rises. As ~he pH rises (or as acidity is reduced) more of the dissociated product, e.g., verapamil lG HCl, is converted, hydrolytically, to undissociated product, e.g., absorbable verapamil free base. ~ecause this conversion is moderated and sustained by successive neutralization of LABS ingredients (the trench bufer phenomenon), the ocular discomfort ass~ciated with l~ instantaneous, total conversion to free base is largely reduced or negated. The average concentration of free base gradually rises as the ocular surface pH rises (due to neutralization of LABS ingredients) until it reaches maximum concentration and then diminishes. It follows, ~herefore, that the plurality of buffers must be qualitatively and quantitatively cus~om tailored to the dissociation profile of the ac~ive ingredients present in a cpecific formulation.
Three factors are simultaneously in play that help avoid overt free base concentration on the ocular surface l) as the free base forms, it is absorbed away from the ocular sur~ace into interior eye tissue t 2 ~
2) the tearfilm activity constantly removes drua product from the ocular surface, and 3) the free base is formed gradually.
The first two phenomena are common to instillation of all eye drops; however, it is the third phenomenon that distinguish~s the activity of LABS from other buffer compositions used to impart comfort to ocular preparations.
- Therefore, the buffering system of the invention can be customized to impart comfort to a specific ophthalmic 10 ~ formulation by adjusting the concentration of each buffer and altering the number of buffers. As a result, an almost infinite number of "comfort patterns" can be devised to effect the controlled conversion of dissociated drug to undissociated drug. The degree of comfort required is a function of the dissociation profile of the active ingredients ~Jith respect to characteristics and degree of free base formed in an environment approximating or somewhat less than pH 7. Stability of a vast majority of active ophthalmic ingredients i5 enhanced in this pH range. So, the pharmaceutical product can be adjusted to a pH range where long-term stability is ensured even if it is significantl~
below the pH of the eye. Consequently, the requirements of stability and comfort can both be addressed without compromising either one.
2~ In another embodiment the ophthalmic solution of the invention may be regarded as an aqueous solution of a medicament in an aqueous ophthalmic vehicle containing an , ,~ .. , .. ., .. . ., ~ ., ., .. ,. ., .. .... , .. ,. ., .. .. . .. , .. .. , .. , .. . . .. ., .. ~ , 4 PCT/U~93~0~549 amount of an ophthalmologically acceptable acidifying reagent sufficient to maintain the solution at an acidic pH in the range of 4. 5-5 . 5 during storage, and an amount of an ophthalmologically acceptable buffer having a pH range between the pH of the solution and the normal pH of the mammalian eye sufficient to cause the pH of the ocular fluid to return gradually to its normal value after a dose of the ophthalmic vehicle i5 instilled into the eye.
The ophthalmic vehicle of the invention may be used to lo '~ formulate medicaments to be administered topically to the eye, when the active ingredients have to be stored at a relatively low pH for stability, but are significantly absorbed only from solutions near physiological pH.
Consequently, the ophthalmic solution of the invention 1, will include an acidifying agent, often referred to in this art as a "buffer", which will adjust the pH of the vehicle to a range suitable for long term storage of the active ingredient, typically pH 4.5-5.5. The acidifying agent will typically be a weak acid, such as boric acid, sorbic acid or the li~.e.
The ophthalmic solution of the invention will include one or more intermediate buffers, i.e., compounds having ~uffering capacity at a pH between the acidic pH to which the vehicle is adjusted for long-term stability of the active 2~ ingredient and the normal pH of the eye, i.e., 7.2-7.~. A
buffer solution, as is well known to those skilled in this art, is one which experiences relatively little change in pH
WO g3/1~76~ PCT/U~93/02549 2 ~ 18 when an acid or base is added thereto. Buffer solutions typically comprise an aqueous solution of a substance which can react with added acid or base to prevent a rapid change - in pH as the acid or base is added. The theory and practice of using buf~ers is well known. A sui~able buffer may be a mixture of a weak acid and its salt, i.e., a partially neutralized wea~ acid. Typically, such mixtures exhibit their ~aximum buffering capacity, i.e., their greatest resistance to change in pH with added acid or base, at a p~
o b- at which the acid is about half neutralized. However, buffers may include materials e.g., water-soluble polymers or organic compounds, for which the theury of their buffering capacity is not so easily expressed mathematically.
Nevertheless, such materials can be investigated experimentally and characterized as to their resistance to change in pH when an acid or base is added to an aqueous solution containing them. Thus, the skilled practitioner can readily identify suitable buffering materials for use in the compositions of this invention. For example, the practi~ioner may select a buffer mixture derived from a weak acid which will be partially neutralized at the desired buffer pH, i.e., an acid having a pKa close to the chosen buffer pH. Alternatively, the practitioner may make use of the knswn properties of water-soluble polymers such as poly(vinylpyrrolidone) or organic compounds such as dextrose.
WO 93/1876~ PCT/US93/0~49 Evidently, the practitioner may select one or more ophthalmologlcally acceptable buffering materials and adjust ~- their concentrations in the ophthalmic solution to achieve the desire~ gradual neutralization when they are instilled into the eye. In particular, a plurality of intermediate buffers may be used, each having effective buffering action at a different pH within the range from the acidic pH at -~hich the ophthalmic solution is kept to enhance its shelf life and the normal pH of the eye, i.e., in the range of 10 ~~ about ;.5 to about 7.2. In such a buffer mixture the pH will rise gradually as the eye neutralizes each buffer material n successlon.
Preferred materials usable in the ophthalmic vehicle of the invention include boric acid as an acidifying agent and, ,; ,~ ,:
as intermediate buffers, disodium eAetate, dextrose, and poly(vinylpyrrolidone)(PVP). Among such buffers, the PvP has ~ `:
been found to have significant buffer capacity at a pH:
between the original acidic pH of the vehicle, i.e., abou~
:
s~ . 5-5 . 5, and the pH of the lacrimal fluids, i.e., 7.2-7.
Si~ilarl~, the disodium edetate, which has a pKa in this ~
range, will be expected to have buffering capacity in this :~;
pH range. Dextrose, as well, can be used a buffer in the pH ;`
range slightly acidic relative to the natural pH of the -~;
lacrimal fluids.
Other ophthalmologically acceptable buffers may also be used in the vehicle of this invention, e.g., phosphate;~
buffers and citrate ~uffers, as well as other weakly WO93/187~4 PCT~VS93/02549 0 ~ -31 ~ ; 20 dissociating acidic substances such as alginic acid, cyclamic acid, edetate calcium disodium, glucuronic acid, sorbic acid and the like.
The amount of intermediate buffer incorporated into the ophthalmic vehicle of the invention should be sufficient to pr~vide enough buffering capacity to cause a relatively slow return of the precorneal lacrimal fluid to the normal physiological pH. The duration of this gradual rise in pH
to be chosen for a particular medicament will depend on the 10 ~~ particular drug used, the concentration of the drug required for therapeutic purposes, and the propensity of the drug to cause ocular discomfort. Typically a duration of about 60 seconds ~7ill provide a period long enough for substantial absorption of the drug while keeping the instantaneous concentration of the free base form small enough to minimize discomfort. However, longer or shorter durationa can be effected by adjusting the concentration of the intermedlate buffers. The choice of concentration of intermediate buffers for a given drug and therapeutic concentration thereof is a matter that can be easily determined by the skilled practitioner.
Use .~,A.
Verapamil HCl in the LABS buffer composition can be administered topically to the external surface of the eye to lowe. elevated intraocular pressure. The effective dose used WO 93/1~764 PCT/US93~025~9 2 ~ ;l D
will vary depending on the particular patient. However, a typical dose will range from about 10 micrograms to about ~ ~
1 milligram per eye per day. ~:
- ~ypically, the concentration of verapamil HCl in the buffer solution will vary from about 0.1 mg/ml to about:~
5 mg~ml. Preferably, the concentration of the solution is adjusted to deliver the desired dose of verapamil HCl in a single drop, e.g., of a-bout 40 micro~iters.
Other embodiments are in the claims. -
Other embodiments are in the claims. -
Claims (24)
1. An aqueous, ophthalmic composition for topical application to the external surface of a mammalian eye for lowering elevated intraocular pressure comprising verapamil, said verapamil being applied to the eye in the form of a stable, dissociated salt (verapamil HCl) at a pH that is low compared to the pH of lacrimal fluid at about 7.2 to 7.4: and a pharmaceutically acceptable ophthalmic vehicle buffered at said pH that is low compared to the pH of lacrimal fluid, said vehicle being capable of controlling the increase in pH of said composition in the presence of lacrimal fluid, said vehicle comprising boric acid, at a concentration of 0.5-3.0%;
disodium edetate, at a concentration of 0.08-0.5%;
dextrose, at a concentration of 0.1-5.0%; and polyvinylpyrrolidone, at a concentration of 1.0-4.0%.
disodium edetate, at a concentration of 0.08-0.5%;
dextrose, at a concentration of 0.1-5.0%; and polyvinylpyrrolidone, at a concentration of 1.0-4.0%.
2. The composition of claim 1 wherein in said vehicle the concentration of said boric acid is 2.8%.
3. The composition of claim 1 wherein in said vehicle the concentration of said disodium edetate is 0.18%.
4. The composition of claim 1 wherein in said vehicle the concentration of said dextrose is 0.3%.
5. The composition of claim 1 wherein in said vehicle the concentration of said polyvinylpyrrolidone is 2.0%.
6. The composition of claim 1 wherein said vehicle is a solution and wherein the concentration of said boric acid is 2.8%, the concentration of said disodium edetate is 0.18%, the concentration of said dextrose is 0.3%, and the concentration of said polyvinylpyrrolidone is 2.0%.
7. The composition of any one of claims 1-6 wherein said vehicle further comprises benzalkonium chloride.
8. The composition of claim 1 wherein said vehicle is a solution and wherein the concentration of verapamil HCl in said solution is such that a therapeutically effective amount of said verapamil HCl can be contained in one drop of said solution of about 40 microliters.
9. An aqueous, ophthalmic composition for topical application to the external surface of the eye with reduced discomfort to the patient, comprising:
an active ingredient for effecting a pharmacological change in the eye or as a diagnostic aid in visualizing ocular structures, said active ingredient being applied to the eye in the form of a stable, dissociated salt at a pH that is low compared to the pH of lacrimal fluid at about 7.2 to 7.4,, said active ingredient being pharmacologically or diagnostically active in its undissociated form as a free base at a pH substantially higher than that in its dissociated form as an ionized salt, and a plurality of buffers in amounts sufficient to arrest the increase in pH of said active ingredient as it changes from a salt to a free base in the presence of said lacrimal fluid, said buffers being differentiated from each other in their buffering capability so that the conversion of said active ingredient from dissociated to free base form is moderated by successive neutralizations of different buffers at different pH levels and the gradual formation of free base imparts to the patient a comfort significantly greater than that present when only a single buffer is used and the change in pH as the active ingredient proceeds from dissociated to undissociated form is a more rapid transition.
an active ingredient for effecting a pharmacological change in the eye or as a diagnostic aid in visualizing ocular structures, said active ingredient being applied to the eye in the form of a stable, dissociated salt at a pH that is low compared to the pH of lacrimal fluid at about 7.2 to 7.4,, said active ingredient being pharmacologically or diagnostically active in its undissociated form as a free base at a pH substantially higher than that in its dissociated form as an ionized salt, and a plurality of buffers in amounts sufficient to arrest the increase in pH of said active ingredient as it changes from a salt to a free base in the presence of said lacrimal fluid, said buffers being differentiated from each other in their buffering capability so that the conversion of said active ingredient from dissociated to free base form is moderated by successive neutralizations of different buffers at different pH levels and the gradual formation of free base imparts to the patient a comfort significantly greater than that present when only a single buffer is used and the change in pH as the active ingredient proceeds from dissociated to undissociated form is a more rapid transition.
10. The composition as claimed in claim 9, in which said buffers are at least three in number.
11. The composition as claimed in claim 10, in which said buffers are selected from the group consisting of boric acid, disodium edetate, PVP and boric acid.
12. The composition as claimed in claim 11, in which said buffers are boric acid, disodium edetate and PVP.
13. The composition as claimed in claim 9, in which said buffers are at least four in number.
14. The composition as claimed in claim 13, in which said buffers are boric acid, disodium edetate, PVP and boric acid.
15. An aqueous, ophthalmic composition for topical application to the external surface of the eye with reduced discomfort to the patient, comprising:
an active ingredient selected from the group consisting of antihistamines, anesthetics, miotics, mydriatics, anti-inflammatories, anti-infectives, timolol maleate, betaxolol HCl and verapamil HCl, said active ingredient being applied to the eye in the form of a stable, dissociated. salt at a pH that is low compared to the pH of lacrimal fluid at about 7.2 to 7.4, said active ingredient being pharmacologically or diagnostically active in its undissociated form as a free base at a pH substantially higher than that in its dissociated form as an ionized salt, and a plurality of buffers in amounts sufficient to arrest the increase in pH of said active ingredient as it changes from a salt to a free base in the presence of said lacrimal fluid, said buffers being differentiated from each other in their buffering capability so that the conversion of said active ingredient from dissociated to free base form is moderated by successive neutralizations of different buffers at different pH levels and the gradual formation of free base imparts to the patient a comfort significantly greater than that present when only a single buffer is used and the change in pH as the active ingredient proceeds from dissociated to undissociated form is a more rapid transition.
an active ingredient selected from the group consisting of antihistamines, anesthetics, miotics, mydriatics, anti-inflammatories, anti-infectives, timolol maleate, betaxolol HCl and verapamil HCl, said active ingredient being applied to the eye in the form of a stable, dissociated. salt at a pH that is low compared to the pH of lacrimal fluid at about 7.2 to 7.4, said active ingredient being pharmacologically or diagnostically active in its undissociated form as a free base at a pH substantially higher than that in its dissociated form as an ionized salt, and a plurality of buffers in amounts sufficient to arrest the increase in pH of said active ingredient as it changes from a salt to a free base in the presence of said lacrimal fluid, said buffers being differentiated from each other in their buffering capability so that the conversion of said active ingredient from dissociated to free base form is moderated by successive neutralizations of different buffers at different pH levels and the gradual formation of free base imparts to the patient a comfort significantly greater than that present when only a single buffer is used and the change in pH as the active ingredient proceeds from dissociated to undissociated form is a more rapid transition.
16. The composition as claimed in claim 15, in which said buffers are at least three in number.
17. The composition as claimed in claim 16, in which said buffers are selected from the group consisting of boric acid, disodium edetate, PVP and boric acid.
18. The composition as claimed in claim 15, in which said buffers are present in substantially equal amounts.
19. The composition as claimed in claim 15, in which the pH
of said solution prior to instillation is about 3.
of said solution prior to instillation is about 3.
20. The composition as claimed in claim 19, in which the pH
of said solution one minute after instillation is greater than 6.5.
of said solution one minute after instillation is greater than 6.5.
21. The composition as claimed in claim 20, in which the pH
of said solution 30 seconds after instillation is less than 6.5.
of said solution 30 seconds after instillation is less than 6.5.
22. An aqueous ophthalmic composition for topical administration of a medicament to a mammalian eye comprising an ophthalmic medicament in a vehicle comprising an aqueous solution containing an amount of an ophthalmologically acceptable acidifying reagent sufficient to maintain said solution at an acidic pH
in the range of 4.5-5.5 during storage, and an amount of an ophthalmologically acceptable buffer having a pH buffering range between the pH of the solution and the normal pH of the mammalian eye sufficient to cause a gradual neutralization of the vehicle by the tears of the eye when a dose of the ophthalmic vehicle is instilled into the eye.
in the range of 4.5-5.5 during storage, and an amount of an ophthalmologically acceptable buffer having a pH buffering range between the pH of the solution and the normal pH of the mammalian eye sufficient to cause a gradual neutralization of the vehicle by the tears of the eye when a dose of the ophthalmic vehicle is instilled into the eye.
23. The use of an aqueous solution comprising an ophthalmic medicament in an aqueous vehicle containing an amount of an ophthalmologically acceptable acidifying reagent sufficient to maintain said solution at an acidic pH
in the range of 4.5-5.5 during storage, and an amount of an ophthalmologically acceptable buffer having a pH buffering range between the pH of the solution and the normal pH of the mammalian eye sufficient to cause a gradual neutralization of the vehicle by the tears of the eye when a dose of the ophthalmic vehicle is instilled into the eye, for the treatment of ophthalmic conditions by topical administration of said solution to the eye.
in the range of 4.5-5.5 during storage, and an amount of an ophthalmologically acceptable buffer having a pH buffering range between the pH of the solution and the normal pH of the mammalian eye sufficient to cause a gradual neutralization of the vehicle by the tears of the eye when a dose of the ophthalmic vehicle is instilled into the eye, for the treatment of ophthalmic conditions by topical administration of said solution to the eye.
24. The use of Claim 23 wherein said medicament is verapamil hydrochloride and said solution is used for treating glaucoma.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US85324692A | 1992-03-18 | 1992-03-18 | |
| US07/853,246 | 1992-03-18 | ||
| US99199592A | 1992-12-17 | 1992-12-17 | |
| US07/991,995 | 1992-12-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2102110A1 true CA2102110A1 (en) | 1993-09-19 |
Family
ID=27127128
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2102110 Abandoned CA2102110A1 (en) | 1992-03-18 | 1993-03-18 | Verapamil hci formulation and other ophthalmic solutions with buffer system for ocular administration |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0589020A4 (en) |
| AU (1) | AU3926093A (en) |
| CA (1) | CA2102110A1 (en) |
| CZ (1) | CZ260093A3 (en) |
| HU (1) | HUT67631A (en) |
| SK (1) | SK143893A3 (en) |
| WO (1) | WO1993018764A2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1312380B1 (en) * | 2000-06-19 | 2006-05-03 | Santen Pharmaceutical Co., Ltd. | Aseptics |
| US7022740B2 (en) | 2004-04-29 | 2006-04-04 | Leonard Mackles | Lubricious ophthalmic solutions |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4470965A (en) * | 1982-10-27 | 1984-09-11 | Usv Pharmaceutical Corporation | Celiprolol for the treatment of glaucoma |
| US4981871A (en) * | 1987-05-15 | 1991-01-01 | Abelson Mark B | Treatment of ocular hypertension with class I calcium channel blocking agents |
| TW200402B (en) * | 1990-08-13 | 1993-02-21 | Senju Pharma Co |
-
1993
- 1993-03-18 HU HU9303263A patent/HUT67631A/en unknown
- 1993-03-18 EP EP19930908438 patent/EP0589020A4/en not_active Withdrawn
- 1993-03-18 CA CA 2102110 patent/CA2102110A1/en not_active Abandoned
- 1993-03-18 CZ CZ932600A patent/CZ260093A3/en unknown
- 1993-03-18 SK SK1438-93A patent/SK143893A3/en unknown
- 1993-03-18 AU AU39260/93A patent/AU3926093A/en not_active Abandoned
- 1993-03-18 WO PCT/US1993/002549 patent/WO1993018764A2/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0589020A1 (en) | 1994-03-30 |
| WO1993018764A2 (en) | 1993-09-30 |
| AU3926093A (en) | 1993-10-21 |
| SK143893A3 (en) | 1994-05-11 |
| EP0589020A4 (en) | 1994-07-06 |
| CZ260093A3 (en) | 1994-07-13 |
| HUT67631A (en) | 1995-04-28 |
| WO1993018764A3 (en) | 1993-11-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1332811C (en) | Treatment of ocular hypertension with class i calcium channel blocking agents | |
| CA2181048C (en) | A method for sustained and extended corneal analgesia | |
| EP0868186B1 (en) | Use of certain isoquinolinesulfonyl compounds for the treatment of glaucoma and ocular ischemia | |
| CA2502437C (en) | Method and composition containing latanoprost for treating ocular hypertension and glaucoma | |
| CA2763778C (en) | Aqueous pharmaceutical compositions containing borate-polyol systems | |
| EP0126684B1 (en) | Drug delivery system utilizing thermosetting gels | |
| AU2009225931B9 (en) | Aqueous pharmaceutical compositions containing borate-polyol complexes | |
| CA2186734A1 (en) | Ophthalmic composition with decreased viscosity | |
| US5760077A (en) | Topical ophthalmic analgesic preparations for sustained and extended corneal analgesia | |
| US6350781B1 (en) | Method and analgesic preparations for sustained and extended corneal analgesia with subanesthetic concentrations of lidocaine | |
| AU688854B2 (en) | Compositions for treatment of glaucoma comprising pilocarpine and a beta-blocker | |
| CA2102110A1 (en) | Verapamil hci formulation and other ophthalmic solutions with buffer system for ocular administration | |
| US4764530A (en) | Pharmaceutical compositions and their use as mydriatics | |
| AU617479B2 (en) | Antiglaucoma compositions containing combinations of sympathomimetic agents and beta-1 selective beta-blockers | |
| US5733938A (en) | Combination of levobunolol and dipivefrin for topical ophthalmic use | |
| JPH06511014A (en) | Ophthalmic solutions, such as verapamil hydrochloride formulations containing a buffer system, for administration to the eye | |
| Noske | Cycloplegic refraction using atropine minidrops | |
| EP0606393A1 (en) | Topical ophthalmic compositions comprising 4-(3-substituted amino-2-hydroxypropoxy)-1,2,5-thiadiazoles and methods for their use | |
| WO2002062344A1 (en) | Method of administering ophthalmic fluids |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |