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A topical composition comprising an amount of a carbonic anhydrase inhibitor and an amount of β-cyclodextrin derivative effective in increasing the bioavailability of the carbonic anhydrase inhibitor when coadministered topically to the eye.
1. An ophthalmic eye drop dispenser comprising a topical, ophthalmic composition comprising an ophthalmically effective amount of carbonic anhydrase inhibitor and an amount of amorphous β-cyclodextrin effective in increasing the bioavailability of the carbonic anhydrase inhibitor when coadministered topically to the eye.
2. An ophthalmic eye drop dispenser comprising a topical, ophthalmic composition comprising an ophthalmically effective amount of carbonic anhydrase inhibitor and an amount of amorphous β-cyclodextrin effective in increasing the solubility of the carbonic anhydrase inhibitor in the composition in comparison to its solubility in the absence of the amorphous β-cyclodextrin.
3. The eye drop dispenser of claim 1, wherein the carbonic anhydrase inhibitor is a heterocyclic sulfonamide.
4. The eye drop dispenser of claim 3, wherein the heterocyclic sulfonamide is acetazolamide or methazolamide.
5. The eye drop dispenser of claim 4, wherein the amount of acetazolamide or methazolamide is effective in reducing intraocular pressure by 20% or more when topically administered in the eye of a person.
6. The eye drop dispenser of claim 5, wherein the amount of acetazolamide is about 0.1 to about 3.5 w/v %.
7. The eye drop dispenser of claim 1, wherein the β-cyclodextrin is hydroxypropyl-β-cyclodextrin.
8. The eye drop dispenser of claim 7, wherein the amount of hydroxypropyl-β-cyclodextrin is about 40-60 w/v %.
9. The eye drop dispenser of claim 1, wherein the β-cyclodextrin derivative is hydroxypropyl-β-cyclodextrin and the carbonic anhydrase inhibitor is acetazolamide or methazolamide.
10. The eye drop dispenser of claim 9, wherein the amount of hydroxypropyl-β-cyclodextrin is about 40-60 w/v %.
11. A method of treating an eye disorder treatable by administering a carbonic anhydrase inhibitor, comprising topically administering to an eye in need of such treatment a topical, ophthalmic composition comprising an ophthalmically effective amount of carbonic anhydrase inhibitor and an amount of amorphous β-cyclodextrin effective in increasing the bioavailability of the carbonic anhydrase inhibitor when topically administered to the eye.
12. The method of claim 11 for inhibiting fluid secretion in the eye or treating an intraocular pressure disorder.
13. The method of claim 11 for treating glaucoma.
14. The method of claim 11, wherein the carbonic anhydrase inhibitor is a heterocyclic sulfonamide.
15. The method of claim 14, wherein the heterocyclic sulfonamide is acetazolamide or methazolamide.
16. The method of claim 11, wherein the β-cyclodextrin is hydroxypropyl-β-cyclodextrin.
17. The method of claim 16, wherein the amount of hydroxypropyl-β-cyclodextrin is about 40-60 w/v %.
18. The method of claim 17, wherein the carbonic anhydrase inhibitor is a heterocyclic sulfonamide.
19. The method of claim 11, wherein the β-cyclodextrin is hydroxypropyl-β-cyclodextrin and the carbonic anhydrase inhibitor is acetazolamide or methazolamide.
20. The method of claim 19 for treating glaucoma.
21. A topical ophthalmic composition comprising an ophthalmically effective amount of carbonic anhydrase inhibitor and 40-60 w/v % of amorphous β-cyclodextrin, said amount of β-cyclodextrin being effective to increase the bioavailability of the carbonic anhydrase inhibitor upon topical administration.
22. A composition of claim 21, wherein the β-cyclodextrin is hydroxypropyl-β-cyclodextrin.
23. A composition of claim 22, wherein the carbonic anhydrase inhibitor is acetazolamide or methazolamide.
24. The composition of claim 22, wherein the carbonic anhydrase inhibitor is a heterocyclic sulfonamide.
25. A composition of claim 21, wherein the carbonic anhydrase inhibitor is acetazolamide or methazolamide.
26. A composition of claim 21, not useful for parenteral administration.
27. A method of treating an eye disorder treatable by administering to an eye in need of such treatment an ophthalmically active agent, comprising topically administering to the eye a topical, ophthalmic composition comprising an effective amount of ophthalmically active agent effective in treating said disorder and an amount of hydroxypropyl-β-cyclodextrin effective in increasing the bioavailability of the ophthalmically active agent when topically administered to the eye.
28. A method of claim 27, wherein the amount of hydroxypropyl-β-cyclodextrin is the amount of about 40-60 w/v %.
29. A topical ophthalmic applicator comprising a topical, ophthalmic composition comprising an ophthalmically effective amount of carbonic anhydrase inhibitor and an amount of amorphous β-cyclodextrin effective in increasing the bioavailability of the carbonic anhydrase inhibitor when coadministered topically to the eye.
This invention relates to compositions of an active agent and a β-cyclodextrin derivative which are topically effective in treating eye conditions.
Glaucoma is a degenerative disease of the eye characterized by optic nerve loss, often in a characteristic nerve fiber bundle configuration. If untreated, glaucoma will eventually lead to blindness. More than 1% of Americans over the age of 40 suffer from this potentially blinding condition. Black Americans are 4 times more likely to suffer from glaucoma and 6-8 times more likely to be blind from glaucoma than are white Americans. The most important risk factor for glaucomatous optic nerve damage is elevated intraocular pressure (IOP). Although there is a real, albeit low, risk of glaucoma in persons with normal IOP (i.e., 16 mm Hg), the glaucoma risk in persons with even mild elevation of IOP (i.e., >22 mm Hg) is elevated 10-fold. When IOP is over 28 mm Hg, the glaucoma risk is approximately 40-fold higher than when IOP is normal.
Four major classes of pharmacologic agents are currently employed to lower IOP on a chronic basis: β-adrenergic blockers, miotics, α-adrenergic agonists, and carbonic anhydrase inhibitors. However, none of the currently available pharmacologic agents is entirely satisfactory. At least 10% of glaucoma sufferers require laser and/or incisional surgery, in addition to medical therapy, to achieve adequate control of IOP. Even when pharmacologic control is possible, the side effects of current agents, combined with poor patient compliance, limit their effectiveness.
Miotic agents, of which pilocarpine is the most frequently used, lower IOP by increasing aqueous outflow through the trabecular meshwork of the eye. Although their topical use is associated with minimal systemic side effects, they frequently cause objectionable ocular and periocular effects. Miotic agents generally cause pupillary constriction, which severely diminishes night vision, and also induce myopia (near-sightedness). Often patients will complain of an objectionable headache or browache associated with topical administration of these compounds.
β-adrenergic blocking agents, of which timolol is the most frequently used, lower IOP by decreasing aqueous secretion. At least five different β-adrenergic blockers are in topical use in the United States with comparable effectiveness. A reduction of up to 25% in IOP can generally be expected when starting a patient on therapy with these agents. Although the β-adrenergic blockers have few ophthalmologic side effects, their systemic side effects can be severe, and occasionally fatal. Topically administered ophthalmologic β-adrenergic blockers can have the same spectrum of systemic side effects as those administered orally or parenterally. Presumably this is a function of drainage through the nasolacrimal duct with absorption across the nasal mucosa. Side effects include heart failure, bradycardia, bronchospasm, dizziness, syncope, depression, dementia, and impotence. At least 10% of patients begun on topical β-adrenergic blockers experience one or more of these symptoms, and there is a widely held belief that greater prevalence of these side effects goes unrecognized.
The α-adrenergic agonist class of compounds is best exemplified by epinephrine and related compounds. While they are used topically in the form of eye drops, in general, they exert less of a pressure-lowering effect than other classes of agents. Patients frequently develop sensitivity to epinephrine and dipiviphrine when used for a year or longer.
Although considerable effort has been directed towards developing topically active carbonic anhydrase inhibitors, they are currently available only for systemic use. While extremely effective at lowering pressure, they often cause numbness and tingling, gastrointestinal upset, depression, lethargy, loss of appetite, and general malaise. These, in addition to the occasional severe systemic reaction, such as aplastic anemia, are so common that many physicians are reluctant to routinely prescribe carbonic anhydrase inhibitors for long-term use.
While investigators have long realized the benefits that would accompany topical administration of carbonic anhydrase inhibitors, the selection of the proper coformulation entity has long eluded them. Most reports in the literature indicate that carbonic anhydrase inhibitors are inactive topically because they cannot cross the cornea. See, for example, U.S. Pat. Nos. 4,888,168 (e.g., column 1, lines 30-36), and 4,619,939 (e.g., column 3, lines 50-53). In some cases, even direct injection of carbonic anhydrase inhibitors into the anterior chamber has been shown to have no pressure lowering effect.
Because carbonic anhydrase inhibitors have a profound effect in altering basic metabolism, the avoidance of a systemic route serves to diminish, if not entirely eliminate, those side effects caused by metabolic acidosis such as hypokalemia, numbness, tingling, general malaise, etc.
Silvistrini, "Effects of Topically Instilled Drugs on Intraocular Pressure in Rabbits", Arzeim.-Forsch. (Drug Res.) 25, Nr. 5 (1975), teaches that the disodium salts of acetazolamide can be used to lower the intraocular pressure of the normal rabbit eye. Silvestrini and subsequent investigators fail to confront the problem associated with the high pH of disodium salt solutions and the significant probability of severe irritation. Attempts to buffer the solutions to a near-physiologic pH generally lead to precipitation of the metal salt.
On the other hand, there is a large body of disclosure supporting the use of cyclodextrin compounds, especially hydroxypropyl-β-cyclodextrin, as excipients for solubilizing non-polar molecules, including a variety of pharmaceutical agents. Hydroxypropyl-β-cyclodextrin (HPBCD) and its preparation by propylene oxide addition to β-cyclodextrin was described in Gramera et al., U.S. Pat. No. 3,459,791. Gramera et al. specifically teach the use of HPBCD to alter the solubility of desirable guest molecules, such as flavoring agents or pharmaceutical agents (column 6, lines 34-37).
Much more recently, Pitha, U.S. Pat. No. 4,596,795, disclosed that the amorphous nature of particular β-cyclodextrin derivatives contributed to the solubilizing effect. Likewise, Muller et al., WO85/02767, disclosed that hydroxyalkyl ethers of β-cyclodextrin are useful for dissolving sparingly water-soluble drugs and for increasing their bioavailability. All examples of the β-cyclodextrin composition in Muller et al. were low viscosity aqueous solutions of between 5% and 7.5% of the β-cyclodextrin derivative combined with 1% or less of the active agent. Muller et al. specifically teaches (Example 7) that when a 0.75% solution of lidocaine, a highly water-soluble compound is constituted in a 5% or 7.5% solution of hydroxypropyl-β-cyclodextrin, there is an increase in bioavailability, as measured by duration of anesthetic effect.
Jansen et al., Chemical Abstracts, CA115(2):15428n, disclose the potential use of β-cyclodextrin derivatives in ophthalmic preparations. Although they found that dimethyl-β-cyclodextrin is toxic to the rabbit corneal epithelium, 12.5% HPBCD was tolerated by the cornea when applied topically. However, when the effect of β-cyclodextrin on the bioavailability of topically administered carbonic anhydrase inhibitor, L-671152, was studied, Grove et al., Chemical Abstracts, CA116:27958u, showed that β-cyclodextrin at either 3% or 1.5% reduced ocular bioavailability to about 50% as compared to when the inhibitor was administered alone.
The present invention provides a method of solubilizing active agents to make them more bioavailable, especially those which are sparingly water-soluble, by combining these agents with β-cyclodextrin derivatives. The combination of active agent and β-cyclodextrin derivative is especially advantageous for topical use in the eye. A carbonic anhydrase inhibitor is a preferred example of an active agent.
The present invention provides an ophthalmic eye drop dispenser comprising a topical, ophthalmic composition comprising an effective amount of a carbonic anhydrase inhibitor and an amount of an amorphous β-cyclodextrin effective in increasing the bioavailability of the carbonic anhydrase inhibitor when coadministered topically to the eye. The present invention also provides an ophthalmic eye drop dispenser comprising a topical, ophthalmic composition comprising an effective amount of a carbonic anhydrase inhibitor and an amount of an amorphous β-cyclodextrin effective in increasing the solubility of the carbonic anhydrase inhibitor in the composition, in comparison to its solubility in the absence of the amorphous β-cyclodextrin.
The present invention also relates to a topical, ophthalmic composition comprising an effective amount of a carbonic anhydrase inhibitor and 40-60 w/v % of an amorphous β-cyclodextrin, said amount of β-cyclodextrin being effective to increase the bioavailability of the carbonic anhydrase inhibitor upon topical administration.
The compositions of this invention are also effective in prolonging the therapeutic effect of the agent when administered to the eye.
The present invention further relates to a method of treating an eye disorder by administering a carbonic anhydrase inhibitor, comprising topically administering to the eye a topical, ophthalmic composition comprising an effective amount of a carbonic anhydrase inhibitor and an amount of β-cyclodextrin derivative, especially hydroxy-propyl-β-cyclodextrin (HPBCD), effective in increasing the bioavailability of the carbonic anhydrase inhibitor when topically administered to the eye. The method can be used to treat intraocular pressure disorders, glaucoma, hypersecretion of fluid by the ciliary body, and other disorders which affect the eye.
The invention especially relates to carbonic anhydrase inhibitors that are hereby for the first time rendered topically effective in the treatment of elevated intraocular pressure. Particularly, it relates to compositions comprising acetazolamide, methazolamide, and related compounds dissolved in a high efficiency preparation of HPBCD. When these preparations are applied topically to the eye, the active agent enters the aqueous humor via the cornea and inhibits the action of carbonic anhydrase in the ciliary body epithelium. The effect of this inhibition is to decrease the carbonic anhydrase-dependent secretion of aqueous humor. Inhibition of aqueous humor production is known to decrease intraocular pressure in many forms of glaucoma and ocular hypertension.
Various other objects, features, and attendant advantages of the present invention will be more fully appreciated as the same becomes better understood when considered in conjunction with the accompanying drawings, in which like reference characters designate the same or similar parts throughout the several views and wherein:
FIG. 1 shows the effect of a 1% acetazolamide solution, alone and in combination with 45% HPBCD, on intraocular pressure (IOP) when administered topically to the eye;
FIG. 2 shows a comparison between the effects of 45% HPBCD and 45% HPBCD in combination with a 1% acetazolamide solution on intraocular pressure (IOP);
FIG. 3 shows the effect of a 2% acetazolamide solution, alone and in combination with 45% high efficiency HPBCD, on intraocular pressure (IOP) when administered topically to the eye; and
FIG. 4 shows the effect of topical administration of a 1% methazolamide solution combined with 45% HPBCD on intraocular pressure (IOP).
In investigating the ability of various therapeutic agents to reduce intraocular pressure, it has been determined that surprisingly high reductions in intraocular pressure can be achieved when the therapeutic agent is coadministered with certain β-cyclodextrin derivatives. The reduction in intraocular pressure is much greater than expected when the agent is administered topically to the eye alone. These novel and surprising results contradict the current teachings and enable the formulation of novel therapeutic compositions comprising β-cyclodextrin derivatives for topical use in the eye. In particular, a composition comprising a carbonic anhydrase inhibitor and hydroxypropyl-β-cyclodextrin (HPBCD) is unexpectedly efficacious in reducing intraocular pressure when administered to the eye, despite the inability of the prior art to successfully formulate these active ingredients for topical administration.
The compositions of the present invention comprise a β-cyclodextrin derivative and an active agent, formulated together for topical administration to the eye. The invention provides a useful and efficient way of administering agents to the eye for diagnostic, prophylactic, and therapeutic uses. Sparingly water-soluble therapeutic agents are especially benefitted, including those which heretofore were not administrable to the eye. The compositions can be used in the treatment of any animal, e.g., horses, cows, rabbits, dogs, cats, birds, etc., especially mammals, including humans. Typically, they are provided in an ophthalmic eye-drop dispenser for topical delivery to the eye, e.g., a squeeze bottle, a bottle/dropper combination, an eye dropper, etc. However, any topical ophthalmic applicator may comprise the composition of this invention, including conventional ophthalmic inserts, implants, ointments, salves, polymers, gels, and the like. See, e.g., Physicians' Desk Reference for Ophthalmology (1982 Edition), published by Medical Economics Company, Inc., Oridell, N.J.; see, e.g., pages 112-114.
A composition comprising a carbonic anhydrase inhibitor and a β-cyclodextrin derivative is a preferred embodiment of the present invention. In particular, the carbonic anhydrase inhibitor is a sulfamide, including, e.g., a heterocyclic sulfamide or alkali metal salts thereof, as disclosed in U.S. Pat. No. 4,438,123; compounds of U.S. Pat. No. 4,619,939, such as 2-orthochlorophenylthiadiazole-5-sulfonamide or 2-trifluoroacetylimino-3-methyl-Δ2 -1,3,4-thiadiazoline-5-sulfonamide; methazolamide analogs of U.S. Pat. Nos. 4,636,515 and 5,104,887; compounds of U.S. Pat. No. 4,975,446; compounds of U.S. Pat. No. 5,055,480; prodrugs of U.S. Pat. No. 5,095,026, such as 2-benzothiazolesulfonamide; and the carbonic anhydrase inhibitor L-671152 of Grove et al., Chemical Abstracts, CA116:27958u. Especially preferred are acetazolamide and methazolamide.
The carbonic anhydrase inhibitor is present in the composition at a dosage which is able to achieve the desired therapeutic effect, e.g., lowering intraocular pressure. Typically, this is about 0.1 to about 3.5 w/v %, the precise amount not being critical and lower and higher amounts being possible. For acetazolamide and methazolamide, the preferred range is about 1 to about 2 w/v %.
Whereas this disclosure is written primarily in terms of carbonic anhydrase inhibitors, the invention (especially the "high efficiency" aspects discussed below) is applicable to any agent whose bioavailability (in level of effect, duration of effect, etc.), or solubility, is desirably increased, including especially agents for topical administration, most especially active agents desirably administered to the eye. Such active agents include any agent, such as those described, e.g., in U.S. Pat. No. 4,983,586, e.g., especially those at columns 14 and 15. Particularly useful with respect to the eye are steroids, β-adrenergic blockers, α-adrenergics, prostaglandins, and others discussed, e.g., in texts such as Physicians' Desk Reference for Ophthalmology, supra. These are all employable in conventional amounts or, in many cases, lower amounts in view of the enhanced effects achieved by this invention, said amounts being determined routinely. Another advantage of the unique combination of carbonic anhydrase inhibitor, such as acetazolamide, and β-cyclodextrin derivative is that it may be administered in combination with oral and/or parenteral therapy, permitting lower oral/parenteral doses of acetazolamide or other carbonic anhydrase inhibitor to be used, thereby ameliorating adverse side effects of the active agents.
β-cyclodextrin derivatives useful for the present invention are those which are intrinsically amorphous, soluble in hydrophilic solvents, e.g., water soluble, and capable of forming inclusion compounds (guest-host compounds) with active agents which typically are hydrophobic organic molecules, including diagnostic, therapeutic, prophylactic, etc. agents. "Amorphous" has the meaning given in U.S. Pat. Nos. 4,596,795; 4,727,064; and WO 85/02767. The amorphous β-cyclodextrins typically are substituted, e.g., by alkyl, hydroxyalkyl, etc. groups, as described in U.S. Pat. Nos. 3,459,795; 4,727,064; and 4,983,536 and WO 85/02767, by sulfoalkyl groups, as described in U.S. Pat. No. 5,134,127, etc. Any other substituted β-cyclodextrin can also be used in this invention. Typically, amorphous β-cyclodextrin samples will comprise at least two, and usually three or more, different molecules which differ in degree and/or nature of substitution. The derivatives can be prepared by any of the conventional methods disclosed in the aforementioned patents. The hydroxypropyl-β-cyclodextrins (HPBCD) are especially preferred in the topical compositions of the present invention. However, HPBCD includes all analogous β-cyclodextrins containing at least one hydroxypropyl substituent and optionally other moieties.
The β-cyclodextrin derivative, especially HPBCD, increases the bioavailability of the agent when applied topically to the eye. It is especially useful for increasing the bioavailability of agents which are sparingly soluble in water. By "bioavailability," it is meant the degree to which a drug or agent becomes available to the target tissue after its administration to an animal. Thus, an amount of an agent is more available to the eye when it is administered in combination with the amorphous β-cyclodextrin than when that same amount of agent is administered alone or with a different, e.g., lower, concentration of β-cyclodextrin. As a consequence of the increase in bioavailability, e.g., therapeutically effective concentrations of a desired drug are attained in the eye tissue which otherwise could not be achieved, e.g., because of low drug solubility or other reasons. Alternatively, the increased bioavailability permits administration of a lower dosage of the agent than otherwise required in its absence and may be used in conjunction with oral and/or parenteral therapy.
The amount of β-cyclodextrin derivative used in the present invention is effective in increasing the bioavailability of a desired agent when coadministered to the eye. Generally, the solubility of the agent in a solvent, including an aqueous or hydrophilic solventor a hydrophobic gel, e.g., as used on skin, is also increased. Usually aqueous or alcoholic, e.g., ethanolic, systems are employed, optionally including other water-soluble components, as disclosed herein. The amount of β-cyclodextrin derivative is generally in the range of about 35 to about 95 w/v %, preferably 40-60 w/v %, especially for carbonic anhydrase inhibitors, lower and even higher amounts being possible, e.g., 20, 25, 30, 96, etc. w/v % (95 w/v %=95 g diluted to 100 ml). The relatively high content of the β-cyclodextrin derivative is a surprising aspect of this invention in that the prior art noted decreased bioavailability of active agents upon coformulation with lesser amounts of β-cyclodextrins.
In terms of viscosity of aqueous formulation, the amount of β-cyclodextrin can be that sufficient to achieve a viscosity of about four to ten times more than that of water. Generally, the amount of β-cyclodextrin derivative will be that achieving an increase in bioavailability of active agent (compared to a simple aqueous solution of the active agent) of at least about 10%, preferably higher, e.g., 20%, 25%, 50%, or 100%, and most preferably, e.g., two- to ten-fold or higher or increasing the maximum solubility of the agent (same basis) by similar amounts.
By "coadministered," it is meant that the β-cyclodextrin derivative and agent are provided to the target tissue (e.g., the eye) together via administration as a single composition. However, it is within the scope of this invention to administer the agent and β-cyclodextrin derivative individually and essentially concurrently. The precise amount of a β-cyclodextrin derivative effective in increasing bioavailability for a particular application and agent can be routinely determined conventionally, e.g., by performing a simple series of parametically varied experiments comparing ability of an amount of agent to enter the eye tissue. Example 1 provides one possible visual method of determining bioavailability, and Example 2 provides a possible physiological method of determining bioavailability. More precise methods are routine, e.g., involving measurements of parameters with the most sensitive methods and equipment available.
The solubility of the active agent can be determined by any of the conventional methods available. For example, solutions of the agent, prepared with and without a β-cyclodextrin derivative, can be filtered (e.g., using a 0.22 or 0.45 μm membrane filter) to eliminate undissolved agent, and subjected to chromatography (e.g., reverse-phase HPLC) to determine the concentration of agent present in the solution.
When the β-cyclodextrin derivative is coadministered to the eye with an active agent in amounts which are effective to increase the agent's bioavailability, the amount of β-cyclodextrin is also effective in prolonging the active effect (therapeutic, prophylactic, etc.) of the agent. The ability to prolong an agent's bioactivity is especially advantageous because, e.g., it permits such agents to be administered less frequently than otherwise required. By prolongation of the effect, it is meant that the duration of time during which an agent is active (i.e., biologically, therapeutically, etc.) is increased when it is coadministered with a β-cyclodextrin derivative. The quantity of time by which the β-cyclodextrin derivative "prolongs" the effect of the agent, e.g., the carbonic anhydrase inhibitor, is not critical because any improvement in the time period during which an agent is therapeutically effective in the eye is beneficial. For example, the composition of a carbonic anhydrase inhibitor, e.g., acetazolamide or methazolamide, and a β-cyclodextrin derivative, e.g., HPBCD, reduces intraocular eye pressure topically for a longer period of time as compared to the carbonic anhydrase inhibitor topically administered by itself. By way of illustration, Example 2 (see FIG. 1, especially) shows that hours after the reduction in intraocular pressure caused by acetazolamide, alone, has returned to normal, the intraocular pressure of eyes treated with acetazolamide and HPBCD is still reduced.
The combination of an agent, e.g., a carbonic anhydrase inhibitor such as acetazolamide or methazolamide, and a β-cyclodextrin derivative can be prepared routinely conventionally, e.g., by mixing the two ingredients together by, e.g., stirring, sonicating, vortexing, shaking, or heating.
The agents of this invention are administered conventionally as the same, or analogous active agents otherwise formulated are administered, e.g., topically to achieve a desired effect, except conventionally taking advantage of the benefits of this invention, e.g., employing lower dosages, less frequent administration, etc. The pharmaceutical composition of the present invention can thus be administered as a fluid by any conventional method of delivering drop formulation to an eye such as by means of an ophthalmic eye-drop dispenser capable of delivering a unit dosage. A typical volume of a therapeutic drop is about 1/20 ml. Each administration typically involves 1-2 drops but can be more or less, depending on the concentration of the agent in the composition; and, typically, there are 1-4, usually 3 or 4, administrations per day, all routinely determinable. The drops are typically instilled in the inferior cul-de-sac of the eye. A typical dose of carbonic anhydrase inhibitor according to the present invention will be about 3-4 mg/day topically (e.g., for acetazolamide or methazolamide), which, compared to the oral doses for these two agents (1000 mg and 150 mg per day, respectively), dramatically illustrates an advantage of this invention.
A preferred example of the present invention is a preparation of acetazolamide, methazolamide, or a related carbonic anhydrase inhibitor and HPBCD. When high viscosity solutions of HPBCD (i.e., 35 w/v % or higher) are prepared, topically active compositions are formulated that provide significant, sustained, reductions in intraocular pressure with a single administration. These preparations are also stable, non-irritating, and non-toxic.
The topical composition of the present invention can further comprise conventional additives, including, e.g., preservatives, solvents, viscosity formers, anti-microbial agents, tissue compatibility enhancers (e.g., cholesterol), salts, buffers, surfactants, and other conventional compounds typically employed in formulations for the given topical use, e.g., in the eye. The solutions of the invention are also sterile or non-sterile as desired. These commonly employed additives are fully conventional and are described, e.g., in the Physician's Desk Reference for Ophthalmology, supra.
The β-cyclodextrin derivatives of the present invention are preferably those forming a high efficiency composition. The "efficiency" of a composition comprising "guest" (i.e., the active agent) and "host" (i.e., the β-cyclodextrin derivative) molecules is defined herein as the molar ratio between the two, guest/host. Thus, a "high efficiency" β-cyclodextrin derivative will contain (or be capable of containing) more molecules of an active agent than a "low efficiency" β-cyclodextrin derivative. Although both low and high efficiency β-cyclodextrin derivatives are encompassed herein by the term "β-cyclodextrin derivative," and therefore are in the scope of the present invention, the high efficiency derivatives are preferred since they permit solutions having a higher w/v percentage of active agent to be prepared and thus enhance the invention. A particularly preferred high efficiency β-cyclodextrin derivative is HPBCD capable of containing 1.8 w/v % or more of acetazolamide.
High efficiency β-cyclodextrins can be defined herein to be those having a guest/host molar ratio of at least 0.6, preferably at least 0.85, and most preferably at least 1 for compounds such as azetazolamide with relatively high molecular weights, e.g., about 220 or greater. For smaller molecules, e.g., molecular weights less than about 220, more entities can fit in a single cavity, whereby preferred ratios are up to 3:1, for example. It is possible that commercially available samples of β-cyclodextrins will be high efficiency; however, as shown below in Example 3, efficiency can vary. Fortunately, it has now been discovered that efficiency can be increased for a given sample of an amorphous β-cyclodextrin by a routine separation/concentration procedure as discussed below.
Since efficiency is defined as the ratio of guest to host molecules, the more guest molecules contained within the host cavity, the higher the efficiency for the amorphous mixture. For water and other small molecules, more than one guest molecule may fit in the host cavity, and a ratio greater than 1 can be achieved. However, for larger guest molecules, where only one molecule fits inside the host cavity, ratios of less than 1 have been found to occur. This implies that not all the β-cyclodextrin molecules within a given amorphous mixture function as hosts.
For example, for larger molecules such as phenolphthalein (mol. wt.=550) only one molecule is conventionally expected to "fit" in the "cavity" of the cyclodextrin; therefore, the theoretical ratio is 1/1, or equivalent to an efficiency of 1. Since a major use of cyclodextrins per this invention is to solubilize higher molecular weight compounds that have very limited solubility in water, the use of the higher molecular weight phenolphthalein, because of its ease of detection, is suitable as an index of the guest/host ratio for analogous molecules. Other readily detectable compounds can similarly be employed. According to the thrust of the literature, ratios are implied to be 1/1. It is further implied that this ratio remains approximately the same for the 2-hydroxypropyl-β-cyclodextrins, the major type of cyclodextrins proposed for pharmaceutical use because of their much higher water solubility as compared with unmodified β-cyclodextrins and other modified variants.
These principles have been applied to three commercially available samples of 2-hydroxypropyl-β-cyclodextrin prepared by the three different manufacturers. It has been discovered that the manufacturing processes greatly lower efficiencies and that efficiency is guest dependent. The low efficiencies of many currently available 2-hydroxypropyl-β-cyclodextrins are a deterrent to their use in the pharmaceutical industry at least because of the large amount of vehicle that must be administered to deliver a therapeutic concentration of drug, when a therapeutic effect can be attained at all.
Thus, methods have been developed for improvement in efficiency to enhance the use of these compounds for beneficial drug delivery in the treatment of disease.
Examples 3, 6, and 7 illustrate the advantageous nature of utilizing high efficiency β-cyclodextrins in conjunction with this invention.
As can be seen from Example 6, at maximum saturation of phenoltetrabromphthalein, the molar guest/host ratio is much less than theoretical indicating that many of the host molecules have cavities that are not available to guest molecules. Moreover, availability of a cavity to one species of guest molecule such as phenoltetrabromphthalein is not an indication of availability to other molecules such as cholesterol. Thus, the ratio can vary from source to source of β-cyclodextrin and from guest to guest for a given β-cyclodextrin. These findings confirm those of Example 3, wherein the guest/host ratios for each of sources A, B, and C, respectively, are 0.007, 0.008 and 0.011.
Fortunately, it has been discovered that efficiency of a β-cyclodextrin can be enhanced. Such enhanced (high efficiency) β-cyclodextrins are preferred for use in this invention.
Referring to Example 7, palmitic acid is one of many hydrophobic compounds with a density less than that of water which can function as a guest molecule. Displacing water from the cavity of host molecules dissolved in water with palmitic acid will result in the formation of a host-guest complex with a density less than that of the water-filled host molecule. These species complexes of differential densities can then be separated, e.g., by centrifugation as shown in Example 7. The greater amount of palmitic acid in the upper fraction of Example 7 establishes that displacing the heavy water with a compound that has a lower density makes possible the physical separation of those cyclodextrin molecules that can accommodate guest molecules from those that cannot. Harvesting the upper layer therefore provides a fraction of the original β-cyclodextrin sample that has a higher efficiency, i.e., higher ratio of guest to host molecules. Separation of the harvested β-cyclodextrin from the molecule in its cavity can be routinely performed using any applicable conventional technique such as extraction, solubilization/precipitation, volatilization, chromatography, dialysis, and the like. For example, palmitic acid can be extracted by partitioning between ethyl acetate and water, and the more efficient cyclodextrin can be recovered by lyophilization of the aqueous phase.
Thus, in a preferred aspect, this invention employs a β-cyclodextrin which has been pretreated to enhance the guest/host ratio for a given active agent when a given sample of β-cyclodextrin (e.g., 2-hydroxypropyl β-cyclodextrin) has a guest/host ratio which is desirably increased. For example, were the active agent to be palmitic acid, the process of Example 7 could analogously be employed to provide a high efficiency β-cyclodextrin with respect to such active agent. For other active agents having a density different from that of water, analogous centrifugation processes can be used. Of course, where desired, the process can be sequentially applied to the separated high efficiency fraction of a prior iteration until further increases are negligible or a desired efficiency ratio is achieved. Where a density differential does not exist with respect to water for a given active agent, density-based procedures can still be employed using, e.g., solvents other than water, e.g., solutions of water and alcohol, other pure polar solvents, and the like. Alternatively, a given β-cyclodextrin can be rendered more efficient by separation procedures based on a different agent but one which behaves similarly with respect to solubilization by β-cyclodextrin's, e.g., based on results of a few preliminary orientation experiments involving solubility as a function of β-cyclodextrin amount, temperature, etc. Typically, such an analogous agent will have size, shape, polarity, etc. properties similar to that of the agent whose density is the same as or similar to that of water. Such use of an analogous agent of course can always be used even where separation procedures are available for a given agent.
It is also possible that any other physical or chemical property differential between the solvent guest molecule (typically water) and the desired "active" agent guest molecule can be used as the basis for a separation technique to concentrate high efficiency β-cyclodextrin from a mixture of β-cyclodextrin overall having a lower efficiency. Such properties include: electrical (e.g., charge), magnetic (e.g., presence of metal ions), chromatographic, chemical, optical, etc., e.g., even if only with respect to guest molecule portions protruding from the host cavities. Thus, corresponding modalities can be used to effect the separation, e.g, electrophoresis, magnetic fields, chromatography, chemical treatments followed by conventional separation or extraction, extraction per se, optical resolution, etc.
Another strategy for the preparation of high efficiency cyclodextrins is to employ the general principle of affinity chromatography. Thus, a column can be prepared having attached a support or molecule which is to be the guest or an analogous "agent", as described above. Attachment can be through any of the conventional methods, e.g., esterification, amidation, etc. Passage of a sample of β-cyclodextrin through the column will cause the subportion of the latter having the best host characteristics for the bound molecule to be retarded more greatly, thus concentrating the subportion on the column. Routine techniques can be employed to separate the β-cyclodextrin from the column. In one example, a column can employ a 3-β-hemisuccinoyloxycholest-5-ene-N-succimidyl ester to a support. As an aqueous solution of hydroxypropyl-β-cyclodextrin passes through the column, those molecules that can accept cholesterol in their hydrophobic cavity will be retarded and can be harvested separately, either by elution with ethanol or collection as a late fraction from the aqueous wash.
All such β-cyclodextrins produced by such methods are usable in this invention. All will normally be amorphous since it is unlikely that a given resultant high efficiency β-cyclodextrin will comprise only β-cyclodextrins all having the same chemical structure. However, where such a homogeneous β-cyclodextrin is prepared which retains the desired high efficiency properties it is included within the scope of the invention as an "amorphous" β-cyclodextrin, especially where any resultant properties, e.g., crystallinity-based, are not disadvantageous.
As can also be seen above, the term "high efficiency" β-cyclodextrin will include any β-cyclodextrin as long as it has a high guest/host ratio associated therewith for a given guest, irrespective of whether the ratio exists for a β-cyclodextrin mixture prepared conventionally, e.g., commercially available, one of which is prepared by the new efficiency enhancement methods described herein.
While the foregoing has been directed primarily to β-cyclodextrins, the principles of preparation high efficiency versions thereof can be directly applied to other cyclodextrins such as α- or β-cyclodextrins using, e.g., guest molecules appropriate for such hosts.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight.
The entire disclosures of all applications, patents, and publications, cited herein, are hereby incorporated by reference.
Solutions of 2% Na-Fluorescein were prepared in 0.9% Saline, 4.5% HPBCD, and 45% HPBCD (the HPBCD is Type B of Example 3). Each solution was applied to the eye of a New Zealand white rabbit and observed for a period of one hour. The anterior chamber of the eye was examined with a standard blue light source on a slit lamp biomicroscope. As expected, considerable fluorescence was seen in the eye receiving 0.9% saline (control eye) at one hour. In contrast, only minimal fluorescence was observed in the eye receiving the 4.5% cyclodextrin preparation. The eye receiving the 45% cyclodextrin preparation had fluorescence equal to or greater than that observed in the control eye and the fluorescence persisted longer than in the control eye. This example indicates that, while a low viscosity solution of HPBCD may decrease bioavailability of a pharmaceutical agent, a high viscosity solution of HPBCD increases bioavailability.
Solutions of 1% acetazolamide in 45% HPBCD and 1% Na-acetazolamide in 0.9% NaCl were applied to paired right and left eyes of 10 New Zealand white rabbits (the HPBCD is Type B of Example 3). Intraocular pressure was measured with a Perkins applanation tonometer at hourly intervals until all pressures returned to baseline. As seen from FIG. 1, acetazolamide in 45% HPBCD resulted in a 25% reduction of IOP with return to baseline at approximately 6 hours (p<0.01 by paired t-test). In contrast, the Na-acetazolamide in NaCl preparation was associated with only a transient, non-statistically significant lowering of intraocular pressure. As a further control, the acetazolamide/HPBCD preparation was compared with 45% HPBCD alone (control). As before, the acetazolamide/HPBCD preparation resulted in a 25% reduction of intraocular pressure, as compared with the control (FIG. 2). This example shows the value of high-viscosity preparations of HPBCD in solubilizing and increasing the bioavailability of sparingly water-soluble drugs, such as carbonic anhydrase inhibitors.
In order to assess the efficiency of 3 different commercially available preparations of HPBCD, the maximum solubility of acetazolamide (maximum solubility in water: 0.1%) was determined for each. The three sources of HPBCD were (A) Roquette (RE No. 446601), (B) American Maize ("Encapsin"), and (C) Wacker Chemical (BetaW7, HP0.9). The Roquette material gave a maximum solubility of 0.1%, the American Maize product gave 1%, and the Wacker product gave a maximum solubility of 1.8%. This example shows that the use of β-cyclodextrin can increase the maximum solubility of carbonic anhydrase inhibitor in topically active preparations.
Solutions of 1.8% acetazolamide in 45% HPBCD (compound "C" of Example 3) and HPBCD alone (control) were applied to paired right and left eyes of New Zealand white rabbits. Intraocular pressure was measured by applanation tonometry hourly for six hours. Compared with the control eye, intraocular pressure was reduced 60% in the eye treated with 1.8% acetazolamide in β-cyclodextrin (FIG. 3). The pressure reduction achieved is more than twice that achieved with a 1% solution of acetazolamide in normal-efficiency cyclodextrin and far surpasses that which may be achieved with maximally tolerated systemic administration of acetazolamide.
Solutions of 1% methazolamide in 45% HPBCD and the HPBCD alone (control) were applied to paired right and left eyes of New Zealand white rabbits. Intraocular pressure was measured by applanation tonometry until pressures returned to baseline. Compared with the control eye, 1% methazolamide resulted in a 60% reduction in pressure, with return to baseline at 8 hours. These results are shown in FIG. 4. This example illustrates that, when dissolved in HPBCD, methazolamide is more potent and has longer duration of effect than does acetazolamide.
45% (w/v) aqueous solutions of 2-hydroxypropyl-β-cyclodextrin using either source A or B (see Example 3) were prepared, and the maximum solubilities of phenoltetrabromphthalein and of cholesterol were determined per 5.0 ml of solution using standard techniques. Phenoltetrabromphthalein concentration was determined spectrophotometrically at 580 mμ. Cholesterol concentration was determined by both GLC and by liquid scintillation counting using cholesterol of known specific activity. The data are shown below, along with a summary of data from other examples.
______________________________________Maximum Solubility and Guest/Host Molar Ratios ofvarious compounds in 45% Hydroxypropyl-β-Cyclodextrin Phenol- tetrabrom- Choles- Aceta- Metha- phthalein terol zolamide zolamideβ-Cyclo- μg/ mg/ mg/ mg/dextrin ml ratio ml ratio ml ratio ml ratio______________________________________A 11.1 .007 0.08 .0015 >5 >5(Roquette)B 12.5 .008 4.3 .038 20 0.31 10 0.14(A. Maize)C -- -- 20a .16 20 0.31 .21 .21(Wacker)______________________________________ a 26-hydroxy cholesterol used in place of cholesterol
2.25 g of Wacker 2-hydroxypropyl-β-cyclodextrin (Source C of Example 3) was dissolved in D2 O to give a final volume of 5.0 ml. 100 mg of palmitic acid was added to the solution and the mixture placed in an ultrasonic water bath at 60� C. for several hours, after which it was brought to room temperature and filtered through an 0.22 mμ millipore filter to obtain a clear solution. 3.0 ml of the solution was centrifuged at 100,000� g for 3 hours in a Beckman TL-100 centrifuge. Following centrifugation, aliquots of approximately 1.0 ml were removed from the tube to give upper, middle and lower fractions. A 0.1 ml aliquot from each fraction was pipetted into a tube and 1 mg of cholesterol added as an internal standard. Each tube was then partitioned between ethyl acetate and water to extract all of the palmitic acid and internal standard. The amount of palmitic acid in each aliquot was then determined by GLC using a flame detector.
______________________________________ Palmitic AcidFraction μg/0.1 ml______________________________________Upper 41.0Middle 34.0Lower 23.4______________________________________
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
Patent Citations
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Print/E-paper exclusives for Thursday, Dec. 13
Besides the stories you can read at herald-dispatch.com, there are many more stories and features in today's Herald-Dispatch newspaper and e-paper.
NORTHCOTT COURT: Efforts to replace the aging Northcott Court public housing complex on Hal Greer Boulevard with affordable housing elsewhere have suffered a setback. Read more on today's front page.
ONE SPECIAL BIRTHDAY: Hayley Diamond, a student at Ceredo-Kenova Middle School turned 12 years old on 12-12-12. Read more about how she celebrated this unusual occurrence on our Region page.
ECONOMIC DEVELOPMENT TEAM MEETS: A wide range of ideas to help foster economic development in Huntington bubbled to the surface during a meeting Wednesday at City Hall. Read more about the ideas on our Local page.
CULINARY SCHOOL MOVES: ulinary arts students at Mountwest Community and Technical College have moved out of the frying pan and into the fire, according to Larry Perry, director of the school's culinary arts and hospitality management program. Read more about the move on our Local page.
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The Damned United
Directed by Tom Hooper
Columbia Pictures, 2009, £19.99
David Peace's work has been a modern day staple of visual adaptations for the past year or so and the author is one of those writers whose books can often be found on the shelves of those who, as The Daily Telegraph might term it, "don't read books", an explorer of yoof issues to cast alongside Irvine Welsh, Howard Marks and Nicholas Blincoe. In truth, and without wishing to denigrate those authors, Peace's ambition extends beyond this. His GB84 in particular is an exercise in wilful complexity, and the earlier Red Riding Quartet constitutes a dark journey into the underbelly of 1970s Yorkshire; its Life on Mars style beiges and browns obscured by gore and low cloud.
That foursome of novellas was filmed to blistering effect in 2009, and Independent Television hadn't shown anything as disturbing for years, unless you count Gazza and Gary Neville on the sofa during the 2002 World Cup. So, the celluloid release of his most accessible novel, The Damned United, roughly contemporaneous to the third channel's offering last year, was eagerly anticipated. Add in the presence of the often flawless Michael Sheen and the combination would be a winning one for sure?
I finally caught up with the movie on DVD this week, and there's a lot to enjoy. Readers of this website will revel in reflecting on the rise of Derby County from relegation threatened second flighters to English Champions in those few short years of flower power and stacked heels, the old stadia interiors with their grubbiness and flaky plastering are heart warming, those colour shades are still there, and the splicing of classic Match of the Day footage with close ups of on-pitch lookalikes is carried off with comparative aplomb.
Sheen is almost uncanny as Brian Clough himself. Due credit is given to the sidekick's sidekick, Peter Taylor, the building of a team around Dave Mackay and a host of other unheralded but hungry and talented players is marvellously narrated, and the explosive 44 days at Leeds are entertainingly depicted. For a football fan, it's an effortlessly quick hour and a half as the memories and memories of childhood reading of Shoot! annuals come teeming back. Love him or hate him, Clough was an unparalleled legend and his achievements are also without equal: the book doesn't even mention his glory years at Forest and the film affords them but a footnote.
But compared to the groundbreaking, daring drama of the Quartet, it's all knockabout stuff, not quite Doctor in the House, but profoundly lacking in gravitas all the same. The book may be Peace-lite, but it's still a warped story indeed, with all the action taking place in Clough's brain. In contrast, Sheen's Clough is a little too bright eyed and bushy tailed, and accurate as the famous nasal whine initially appears to be, it's exposed as too parodic when Ol' Big 'Ead appears on screen immediately before the closing credits. It's said that the offence taken by the Clough family by the book led to a toning down of the film's ambition, but this compromise leads to a fudge of a film where the swearing seems tacked on and the 1970s are played for laughs. The Leeds of that era was bandit country indeed, but one never senses the danger of that rough, tough city. So, it's a three star effort and a story lovingly recreated, but more punch would have been welcome.


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Sticks Pinot Noir 2008
Pinot Noir from Yarra Valley, Australia
Winemaker's Notes
This Pinot Noir has a vibrant, bright red color with purple hues. The bouquet is one of dark cherry, plum, and red berries with hints of spice. The fresh red berries are evident on the palate with mulberry and spice.
Critical Acclaim
International Wine Cellar - "Light, amber-rimmed red. Spicy, intensely floral aromas of strawberry and cherry, with hints of mint and white pepper. Light-bodied red fruit flavors are silky and focused, with good mineral snap and a hint of cinnamon. I suspect that many will find this wine too light but I like its graceful, light touch and spicy character."
Australian Wine Companion - "Bright colour; a light spicy/savoury style which needs more mid-palate vinosity."
Sticks Winery
Winemaker Rob "Sticks" Dolan crafts these wines from fruit grown on premium vineyards in Victoria's Yarra Valley. Rob Dolan's career began in South Australia, where he learned the art of making wine from the ground up. He developed and refined his skills under the instruction of two of Australia's most distinguished teachers. It was during this time that the budding winemaker and towering sportsman, known as "Sticks", was also a dual premiership player for the Port Adelaide Football Club.
In 1991, Rob Dolan became the winemaker at Yarra Ridge. The small family winery provided Rob with the opportunity to experiment, which enabled him to hone his winemaking skills. His efforts were immediately recognized on the international show circuit. Rob proceeded to plant his first "Sticks" grapes in the mid 1980's. The goal at Sticks is to provide today's drinker with immensely satisfying wines at affordable prices. View all Sticks Wines
About Yarra ValleyView a map of Yarra Valley wineries
A short drive from Melbourne, Yarra Valley is the oldest and most successful of Victoria's wine growing regions. The cool climate of the area makes it suitable for the popular varieties of Pinot Noir & Chardonnay. Shiraz also thrives, and produces elegant and restrained versions of the varietal.
Notable FactsProducers in Yarra Valley have hit their stride when it comes to Pinot Noir and Chardonnay. Instead of striving to make wine like Burgundy or California, winemakers are crafting a Yarra Valley style, letting the grapes and the soil do the talking. Getting better each year, Yarra Valley is a region to watch.
About AustraliaLike the United States, which is about the same size, Australia's winemaking regions are huddled into one or two pockets of the country. The state of South Australia, which produces about 60% of the country's wine, also has the most wineries and sub-regions, including McLaren Vale, Clare Valley, Coonawarra and Barossa Valley. New South Wales is home to the Hunter Valley, while the smaller, southern state of Victoria is best known for theYarra Valley. Head way west to the very large state of Western Australia and you'll find the tiny region of Margaret River at the southern tip.
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1 rating, 1 with review24/26/2012This was very dry and sour for a pinot.Related ProductsThe 2012 Wild Ridge Pinot Noir balances the bright acidity and spicy notes considered classic in coastal Sonoma Pinots with ...The 2011 Arcus Estate Pinot Noir opens with aromas of fresh blueberry cobbler, dark plums and juicy black cherries. Succulent ...
Alcohol By Volume GuideMost wine ranges from 10-16% alcohol by volume. Some varietals tend to have higher (for example Zinfandel and Cabernet Sauvignon) or lower alcohol levels (Pinot Noir and many white varietals), but there is always some variation from producer to producer. Some wine falls outside of this range, for instance Port weighs in closer to 20%, while Muscat and Riesling are usually a bit below 10%.
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Book Depository BlogRSS
Here comes the bride
Thu, 17 Mar 2011 13:15
You may have heard of a very happy event coming up at the end of April. It's the wedding of our very own, dear Prince William and his radiant fiance, Ms Kate Middleton. To prepare for and celebrate this wonderful occasion, For Dummies have brought us this charming guide to Royal Weddings past, present and future written by the distinguished editor of the Independent on Sunday, Julian Knight. As an extra special treat Dummies have given us a sample of the book to download for absolutely nothing. That's right, free! You can launch this splendid pamphlet in a new window, here
What you may not realise, however, is just how close we are here in the Book Depository basement (sorry, Lower Ground Floor...) to the elegant shadow of the Castle and all things house of Windsor. Indeed, every other day, our very foundations are shaken by the stirring marching of the changing of the Irish guards. It gives us such a thrill to be able to just about see the boots of the soldiers drilling up and down the street in patriotic fashion.
Anyway, we asked the work experience boy to knock up a handy visual guide to let you all know just how lucky we are...
More Royal Wedding books can be found here...
CommentsShowing 1 to 13 of 13 results
Showing 1 to 13 of 13 results
- Zahidulllah
i invite all the worl to come to the worship of allah subhanahu wata ala
- Posted Fri, 01 Jul 2011 11:04
- Kieron Smith
:( sorry we weren't trying to mislead anyone, we just thought the eBook was a bit amusing and that customers might think so too. We have thousands of free eBooks (complete ones) available at www.bookdepository.co.uk/free should you wish to download one of them instead...
- Posted Fri, 25 Mar 2011 00:44 Under review
- Michael Quall
gee whiz, what a humourless bunch of whackjobs you lot are...
- Posted Thu, 24 Mar 2011 10:11 Under review
- Alistair P D Bain
to those who complained, read the blurbage. it does say - maybe not clearly enough - that it's a 'sample'. yes, the mass of the advertising is misleading - but what does it say about those, myself included, who simply want something for nothing? i think the RW (Royal Wedding) is claptrap, but others find it enthralling - good for them. i hope they like whatever the 'sample' gives them! and no - i haven't and won't be downloading the sucker :-)
- Posted Thu, 24 Mar 2011 05:07 Under review
- Roy Palmer
If anyone in your company thought this was funny, you lost. I won't be back. You don't tell your customers it is free and then let the customer find out it is not the whole deal. Bye
- Posted Thu, 24 Mar 2011 03:31 Under review
- jay
This book is not really free. Only the first 30 pages or so of the book are free. The title of the blog post is misleading as the perception is that you will get the book for free, when in fact it's a free sample.
- Posted Wed, 23 Mar 2011 18:40 Under review
- Deb
This is not a free e-book, it is a free excerpt - 29 pages. You will not, despite the dazzling & alluring promises above, find out from this free excerpt how to plan a royal street party or get a royal trivia quiz, as they are in chapters 8 & 10 of the book, and not included in the free extract. You will however, in addition to a list of royal weddings of the past given a rating out of 10, get your very own personal invitation to *buy* the book. No need to RSVP.
- Posted Wed, 23 Mar 2011 07:04 Under review
- Dan Gee
Is it April 1 already? Is this book for real? Will anyone really read this guff? What next, "the Dummies guide for Dummies"?
- Posted Wed, 23 Mar 2011 02:49 Under review
- Paul
ingrate. I could say this about every book written about a subject that I'm not interested in, but I don't because I not so narrow minded.
- Posted Tue, 22 Mar 2011 19:30 Under review
- Paul
A few interesting facts that I didn't know, thanks.
- Posted Tue, 22 Mar 2011 19:26 Under review
I don't know... who would download this book? Why is this book even written...
- Posted Tue, 22 Mar 2011 13:19 Under review
- Nick Knibb
This is without doubt the most excited I've been since the wedding of Princess Edward. I quite literally cannot wait to sit myself down in front of the telly to watch William take Katherine up the aisle.
- Posted Tue, 22 Mar 2011 12:51 Under review
- Roger Thompson
Very interesting expose of the royal couple (to be) looking forward to the union. Will visit to Aust & NZ has been a great boost to all Down Under.
- Posted Mon, 21 Mar 2011 23:12 Under review
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How to Create Awesome Online Videos: Tools and Software to Make it Easy
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With today's tools, creating professional video is easier than you think.
In this article you'll discover tools and resources to create videos that you can use to market your business right now.
#1: Do It All on Your Apple Device
The newest versions of Apple's iPhone and iPad let you shoot 1080p, HD-quality video using iMovie—their free, built-in moviemaking software. iMovie is fairly simple to use and lets you to create slick videos and upload them to YouTube or Vimeo on the spot.
Before you jump into moviemaking, first make sure you have a method for holding the iPhone or iPad steady. (Nothing is more distracting than a shaky camera!) Use an after-market tripod attachment or add-on to ensure you get steady shots with your mobile device.
How Online Video Can Grow Your Business and Your Brand
In this video I interview Steve Garfield, who is the author of the book Get Seen: Online Video Secrets to Building Your Business.
Steve shares insights into how video can give your company a competitive advantage. He also shares tips on how to get started and what to look out for in the future.
Be sure to check out the takeaways below after you watch the video.


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This World of Ours – Review
Before I get into my review of This World of Ours, I thought it would be interesting to point out a very some very interesting facts pertaining to the director. I believe it is significant to the film as well as my overall review. Director Ryo Nakajima wrote the script for this film at only 19 years of age, and filmed it when he was 23. Previous to his experience in film-making, he was what the Japanese call a "hikkimori"—a reclusive individual who have chosen to withdraw from social life—and spent numerous years in a self-imposed isolated state. Upon arriving at the end of his emotional handicap, Ryo believed it was his duty to share his thoughts deriving from his experience as well as his opinion regarding Japanese society—from his perspective—and thus This World of Ours was born.
When a film such as This World of Ours opens with distorted footage of the destructive aftermath of 9/11, you know you're in store for something more than your mere standard film. This World of Ours follows three characters with interconnected paths—we first have Ryo (Satoshi Okustu), a school bully who learns the error of his ways when he becomes the victim himself; next is Hiroki (Yoshiko Taniguchi), a college student who is learning the harsh realities of either accepting to follow the routine path to adulthood or the not; and finally we have Ami (Arisa Hata), another high school student who must use other people to do her bidden due to her insecurities. Each of their paths will eventually intersect to lead down a singular path of destructive behavior.
This World of Ours is a very interesting and adventurous film to say the least. The strong theme of "youth" as an integral part of society, and how they fit into the entire societal structure is vividly examined—and at times a little exaggerated—but still very much a microscopic critique of Japanese society. The three individuals within the film are all deviants from how their society deems what is "normal" behavior; Ryo doesn't believe school is important, Hiroki is questioning continuing going to school to get a good job, and Ami is insecure about her own exterior looks. These three ideologies represent the fraction of individuals within their society that function through these ideals, whether they believe in their notions or not.
Perhaps this examination relates to elements that director Ryo Nakajima personally endured through his "hikkimori" phase. I could easily see elements within the film that could mirror his disability, and to see the conformist philosophy that is quite heavily instilled in contemporary Japan, it's highly likely that he trying to defer the argument that one must conform or else slip away. The analyzing of these variants bring forth a sort of a sane rationalization of the decisions these character make within the film, perhaps to the point of being brutally honest. I respect this element of the film immensely, and it truly showcases the importance that Nakajima put forth in addressing his characters as people who are slowly trying to obtain their individuality in a society that dismisses it.
This World of Ours is a film that is not only exceptionally well thought out, but also effectively addresses the disillusionment that accompanies an individual's willingness to conform to society. The acting is superb as well, and it truly complements the direction by Ryo Nakajima. For a first time director, this debut is in every sense of the word mesmerizing, and if this is what Nakajima has to offer to the world of Japanese cinema, I'm truly anticipating his future releases.
Author: Miguel Douglas
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Kuklo was found as a baby crying in a mass of Titan vomit, amidst the dead titan corpses. He is essentially hated by the people inside the walls. Kuklo, despite his horrible beginnings and a single-functioning eye, also seems to grow unnaturally fast. He parts himself from his past and gambles on the fate of humanity by enlisting in the Survey Corps.
Aldnoah.Zero – Review
In 1972, an ancient alien hypergate was discovered on the surface of the moon. Using this technology, humanity began migrating to Mars and settling there. After settlers discovered additional advanced technology, the Vers Empire was founded, which claimed Mars and its secrets for themselves. Later, the Vers Empire declared war on Earth, and in 1999, a battle on the Moon's surface caused the hypergate to explode, shattering the Moon and scattering remnants into a debris belt around the planet.
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The story takes place many years in the future where the game "Rhyme," a virtual fighting game, is incredibly popular and people possess "AllMates," convenient AI computers.
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Call Toll Free:
Vintage Airplanes 2014
Vintage Airplanes Calendar
Vintage Airplanes pictures classic aircraft from the golden age of aviation. With photographs and descriptions by Dan Simonsen, each page includes a history of the model. The calendar delights fans of vintage aircraft, while its sales benefit the Golden Air Age Museum, a nonprofit educational institution founded to educate visitors about the early days of aviation.
14 x 22 inches, open
Featured Planes:
- AT-11 Kansan
- Piper J-3 Cub
- Waco UPF-7
- Bücker Bü 131
- Goodyear FG-1D Corsair
- Curtiss JN-4
- Cessna 195A
- Globe Swift
- Curtiss Wright Robin
- Westland Lysander
- Nanchang CJ-6
- PT-17 Stearman
About Vintage Airplanes:
As I look at this year's calendar its truly international flavor stands out. Not only are there aircraft from other countries, but at least one of the images was taken overseas. 2014 has images from England, California, Las Vegas, Alabama, Pennsylvania, and Virginia. While last year's calendar was filled with one of a kind aircraft, this year's calendar is filled with some old favorites from different time periods.
The airplanes range from the early days of post- World War I barnstorming and the roaring twenties to the early post-World War II years. What do all of the airplanes have in common? To me they're all beautiful and they each have their own story. Sometimes the story is in the design of the aircraft, like the Corsair's gull wing design. Sometimes the story is in how the plane was used, like the Lysander, which was used to fly agents into occupied Germany. Sometimes the story is in what paint scheme an owner used on the aircraft, like the Golden Age Air Museum's Curtiss "Jenny" barnstorming paint scheme to reflect the "Jenny's" key role as a barnstorming airplane.
Every airplane has a story to be told and, more importantly, to be heard. The owners of these beautiful airplanes share the story of their airplanes for us to see. They preserve the memory of the yesteryears of aviation by keeping their airplanes flying.
As for me, I get the honor of using my trusty Nikon camera to paint a picture of light on the film. For this, I feel truly lucky.
To photograph this year's 12 calendar beauties, I took somewhere between 100 and 300 positive images (slides), photos or digital images per airplane. So, we're looking at somewhere well over 1,000 images to produce this one calendar. Taking that many photos or digital images presents its own logistical challenges. While last year I joked that a terabyte hard drive just doesn't last as long as it once did, I'll add that buying more hard drives just results in their getting filled and the slides for this year's calendar take up a whole shelf in my closet.
As always, without the help of skilled and dedicated photo-chase pilots, the calendar wouldn't be possible. I took some of these images many years ago and the names of some of my photo-chase pilots have escaped me. If I've forgotten your name I apologize, but I remember your skill and dedication in helping to get the shot. I also must thank: Bill Almond, J.O. Howatt, Les Deline, Denny Hickman, Andrew King, Bill Allen, and Scotty Patterson. It's through their willingness to "chauffeur" me around the sky that these photos are possible. Of course, I also thank the aircraft owners for not only letting me photograph their beautiful aircraft, but for keeping them flying for all of us to see.
I'm always looking for aircraft to photograph. If you'd like your aircraft considered for a future Vintage Airplanes calendar, you can contact me via Tidemark Press; visit my website, www.aviatorphoto.com; or send me an e-mail at email@example.com.
Until then, Blue Skies and Favorable Tailwinds. Let's go fly!
– Dan Simonsen
Vintage Airplanes Calendar Photographs
This beautifully designed publication is attractive and useful, with calendar grids that have large blocks for every day of the week. The monthly calendar also includes grids for the previous and forthcoming months, to make planning more convenient. The Vintage Airplanes calendar opens to a generous 14 by 22 inches, nearly 10 percent larger than most other brands and includes major holidays and phases of the moon. Tide-mark Press publishes distinctive books, cards and calendars. Full-color calendar titles range from nautical, art, and landscape, to trains, planes, and gardening.


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Just a few random bits that I wanted to mention without having separate posts for everything:
First up, Mischa is featured in a French magazine called "Crash". A couple of the shots have shown up online and thanks to Maz, I've uploaded them here. Hopefully the full shoot will surface shortly.
Next up, some news regarding Mischa's film "Don't Fade Away". As we know, Mischa filmed this a couple of years ago and things have been very quiet on it. A recent interview with Ryan Kwanten (Mischa's co-star) has just revealed that they were actually waiting for him to finish filming his series "True Blood" before they could complete principal photography. Ryan's final scenes for "Don't Fade Away" were shot around September 2008 meaning that the film has only recently entered post production. Some other good news is that the film was just picked up for international distribution so we'll hopefully hear some release news over the coming months.
And finally, MISCHA-B.COM just turned 5 years old! January 11th marked the big day and I completely forgot, lol. Here's hoping we have at least another 5 years.
In February's Cosmo, Herbal Essences' new ambassador Mischa Barton shows us how to do Hollywood hair without a superstar salary. Check out these behind-the-scenes snaps from the shoot and as well as her revealing beauty secret.
Do you ever have bad hair days?
"I definitely have bad hair days! My hair's a bit unruly sometimes, so I condition it lots. I don't actually mind messy hair; I quite like a 'tousled' look. My hair doesn't dry completely straight. I don't like it when it looks too perfect, so long as it feels great."
What's your favourite way to wear your hair? Are you quite experimental or conservative with it?
"I change things around, but for the most part I just wear it down and natural – so much gets done to my hair when I'm doing red carpet things or especially when I'm acting, so when I'm not working I really like to give it a break in my free time."
Do you feel pressure to look your best all the time, or do you have a good sense of perspective about it?
"I think it's cooler when girls look themselves, so I don't fuss too much about the way I look – I really dress for me. I think it's important as a girl that the way you dress and the way you look are for yourself and you're not just trying to please other people all the time."
What are you favourite beauty treatments? Do you like going to spas? Which are your favourites?
"I do love a good spa! I love massages and I go for lots of those. And I love a good steam room too. I've been to all kinds of spas – I go to Saturnia in Italy with my family and love visiting the spas around there, and even just the local day spas in LA are great place to escape to."
What's your beauty must-have?
"I'm not really a lip gloss girl, but I really like lip balm, so I normally carry one of those with me (I love By Terry Rose Lip Balm)."
What's your typical beauty routine in the morning and evening?
"I'm not too high-maintenance – I just wash my face morning and night then I just use a good moisturiser, sometimes something with an SPF if I think it's necessary, and I always keep cleansing wipes by my bed to make sure I take my make-up off because otherwise I can be a bit lazy! Otherwise that's pretty much it."
When you feel you need a treat, what is your greatest pleasure?
"Taking some friends for a day at the spa- we always have a great time, it's always really fun and a great way to relax, too."
What energises you if you're feeling tired?
"If I'm feeling really lazy, I'll take a long bath with scented oil or bubble bath. That's when I can't be bothered to stand up in the shower! At the end of a 12-hour day, that's usually where you'll find me! And I'm a champion sleeper, too!"
Cosmopolitan.co.uk | Thanks Marie
Things are kinda slow at the moment but I trust all of you have been checking Mischa's official blog pretty regularly. There are a ton of videos and pictures added all the time!! I'll find some pictures to update this site with shortly.
To celebrate the launch of the official website for Mischa's handbag collection, I've uploaded the three promotional photos of the collection modeled by Mischa herself. Big thanks to Julia! For additional stockists, click here.
International actress and fashion pace setter Mischa Barton is delighted to launch her own Mischa Barton handbag website: www.mischabartonhandbags.com
New for January 2009, the website stocks Mischa's second collection of sought after handbags which include vintage inspired totes, chic mix drawstring bags, small clutches and oversized slouch bags.
Eclectic new styles sit alongside first season favourites re-worked in exciting new leathers and fabrics. There is also a new range of must have purses.
Prices range from £20 to £200.
We met Mischa Barton, the popular OC actress, on the sets of Bhopal: A Prayer for Rain on the final day of their shoot at Golconda Fort in Hyd.
Looking ever-so-graceful in a safari suit, she enacts the role of a foreign journo in the film based on the Bhopal Gas Tragedy.
Earlier in the day, Mischa had been shooting in the Charminar area, (she'd also shopped there earlier and loved the colours on our streets) and happened to notice a dehydrated puppy lying on the road. Mischa picked it up at once, got a vet to attend to it and wanted to take it back with her to the UK.
The entire crew was quite taken up by the 2-month old pup and to everyone who kept asking, "How's he doing?" there was someone correcting, "It's a she!" Mischa was worried about the pup's health all day and rushed to the vet after the shoot on Friday evening.
Totally taken in by the city, the Hollywood actress observed, "Hyderabad is a real inspiration in the fact that Christians, Muslims and Hindus all get along so harmoniously." She is even impressed with the traditional masala chai. "I must admit I used to make fun of people who were all into yoga and chai , thinking it was another ridiculous health fad.
"But now I'm that person! First of all masala chai, the traditional way with milk and sugar is delicious, and this is coming from a Brit who only likes English Breakfast!" she added.
However, the actress is not so pleased with her progress in learning a new musical instrument.
"I must say my goal was to learn to play the sitar and it's coming along real slow as apparently it's not that easy to procure a great sitar teacher here, I guess it's not late 60's with Ravi Shankar and George Harrison roaming around unfortunately!!!!" she added.
A photo shoot of Mischa in her LA home from earlier this year has been uploaded. The shoot was originally featured as a story in OK! magazine (namely as the cover story for OK! Australia). The photos are by Amy Neunsinger.
Pretty sure I haven't added these photos yet, so here is Mischa from August 2006 at a Teen Vogue party to raise awareness for global warming. This is back when Mischa and Rachel Zoe were still close. And a belated Happy New Year to all the visitors!


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I wish there were more peripherals for thunderbolt. I think its adoption was slow and USB 3.0 has become much more popular.
Apple releases stability fix firmware update v1.2 for Thunderbolt
Users of a Thunderbolt equipped Mac will want to head on over to the Apple Support pages and grab the latest firmware update. It's not a huge update, in fact the download is just 1.22MB in size, but does promise stability fixes for Thunderbolt and for Target Disk Mode. And we'll always welcome stability fixes.
A restart of your Mac will be required following install, and to grab the new firmware hit the source link below.
Source: Apple Support
Have something to say about this story? Leave a comment! Need help with something else? Ask in our forums!
Reader comments
Apple releases stability fix firmware update v1.2 for Thunderbolt
Do you have your MBP plugged in? Firmware updates require you to be plugged in or they will simply not install, so it'll act like it's installing, reboot, but then the actual update doesn't complete and so it'll keep showing up.
Oh, yeah that's probably what it is. It warned me, but I thought it was the obligatory warning to plug in, not a requirement. You'd think it would just stall or stop, it actually went through the motions, kinda misleading, anyway my fault for not reading all of it.
Thanks, I'll retry with it plugged in.


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The neighborhood historically maintained lower housing prices than most of the Upper East Side .
The average sales price of a Queens home was $429,544 in the 1st quarter of 2014.
The sales prices for UES apartments increased significantly in the third quarter of 2013, reports showed.
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• Home
• About PDEQ
• Contact Information
• Public Records Request
• News and Events
• Search PDEQ
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• Waste
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• Programs & Info
• Rules & Regulations
• FAQs
• Links
What is a Public Records Request?
What types of records does PDEQ have?
How do I request a PDEQ Public Record?
How do I know if my request is Commercial or Non-Commercial?
Will there be a Fee?
When will PDEQ respond to my Public Records Request?
What will happen next?
Can I come to the office to Review Records?
What does "Tampering With Records" mean?
What is NOT considered a Public Record?
Which statute applies specifically to the County Public Records Process?
Who can I contact for septic, zoning, or building records
Who can I contact if I have questions about PDEQ Public Records Requests?
What is a Public Records Request?
Requests for information to PDEQ generally fall into two categories: general information requests or public records requests.
General Information Request
A general information request may include information about the environment, copies of forms, procedures, pamphlets, or other printed information designed for public distribution. General information requests can be made and answered through a phone call at PDEQ at 724-7400.
Public Records Request
A public records request includes, but is not limited to, documents and electronic files prepared, owned, used, or retained by PDEQ in the course of conducting its work. Under Arizona State law, the public can request in writing to examine or copy public records.
Arizona's public records law should not be confused with the Federal Freedom of Information Act, which applies to records held by federal agencies. Pima County does not have a central repository for all its records. Each department and division within Pima County houses its own records. Please refer to each department's web site for more information. (ARS §39-121)
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What types of records does PDEQ have?
PDEQ maintains records regarding the day-to-day operations for the Environmental Quality Division including the Air, Water and Waste Programs and the Solid Waste Division that oversees the landfills and transfer stations. PDEQ will provide records that are maintained in the format preferred by the requestor for a nominal copying fee. PDEQ records may be paper files, database information, PDF files, Word documents, Excel spreadsheets, engineering plans, microfiche or other format.
PDEQ is not required to create a record that is not maintained in the normal course of doing business, i.e. manipulate data to meet a specific public record request nor is it required to obtain new data, perform research or create new report formats.
PDEQ is a predominantly paperless department that utilizes multiple internal databases to house records. PDEQ files and databases provide the most historically accurate and extensive property search results when using an in situ address. PDEQ is able to provide property records utilizing a parcel number. or township/range/section criteria, however, the record information provided will be limited to the particular search criteria provided.
Click here for Air Program information. Per A.R.S. §49-487, PDEQ maintains an online database regarding stationary source permits.
Click here for an online list of Stationary Source Permits.
Click here for Waste Program information.
Click here for Water Program information.
Click here for Solid Waste Division information.
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How do I request a PDEQ Public Record?
Select, fill out and sign one of the Public Records Reproduction Request Forms (Non-Commercial Form or Commercial Form) and return it to PDEQ. If you are requesting records for non-commercial purposes, you must also fill out and sign the attached Verified Statement for your request to be processed.
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How do I know if my request is Commercial or Non-Commercial?
Please see Public Records Reproduction-A.R.S. § 39-121.03
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Will there be a Fee?
Commercial record requests incur a reproduction fee as listed on the request form. Non-Commercial requests, depending on the type of request may or may not incur a reproduction fee. See the Reproduction Fee Schedule.
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When will PDEQ respond to my Public Records Request?
PDEQ is required to fulfill all reasonable public records requests under Arizona State law. Depending on the complexity and volume of the search, requests can take up to two weeks to be processed. Requests for multiple property searches will have a longer turn around time and may be submitted with one request form that includes an attached list of addresses or parcel numbers.
Commercial requests with a list of properties attached will be charged the commercial fee on a per property basis. All requests are processed in the order in which they are received.
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What will happen next?
Non-Commercial Request
Upon receipt of the request form, PDEQ staff will locate the record(s) and prepare them for dissemination. An invoice of the reproduction fees can be provided with the records.
Commercial Request
Upon receipt of the request form and reproduction fee payment, PDEQ staff will locate the record(s) and contact the requestor with the results and copying costs. An invoice of the reproduction fees can be provided with the records.
Records will not be released until payment is received by PDEQ. Once payment is received, the record will be emailed, faxed, mailed, or picked up at the PDEQ office per requestor's preference.
For property searches and Phase 1 or 2 Environmental Site Assessments (ESA's), once payment is received, a letter detailing the results of the search will be emailed, faxed, mailed, or picked up at the PDEQ office per requestor's preference. After reviewing the letter, the requestor may choose to request copies of the identified records and select what format (such as e-mail, paper or burned on a CD) they want the records delivered in. Records will not be released until payment is received by PDEQ.
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Can I come to the office to review records?
Any person requesting to come to the PDEQ office and review records may do so doing regular business hours. An appointment can be made in advance so staff can retrieve the record and set up a designated reviewing area. The PDEQ Physical Records Review Request Form will need to be completed prior to reviewing the records. The public records reviewing area shall be in view of a PDEQ staff person who is responsible for seeing that no tampering occurs with the records. Depending on the number of copies requested and the available time for staff, copies may be generated while the party waits in the lobby. If this cannot be accomplished, staff will make arrangements with the requesting party for payment and pick-up or delivery of the records.
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What does "Tampering With Records" mean?
A person commits tampering with a public record if, with the intent to defraud or deceive, such person knowingly destroys, mutilates, conceals, removes, or otherwise impairs the availability of any record. Tampering with a public record is a class 6 Felony (A.R.S. §13-2407.C.)
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What is NOT considered a public record?
Certain records are exempt from public disclosure. Documents that may not be considered public records and therefore may not be available include:
Which statute applies specifically to the County public records process?
Please see Public Records Reproduction-A.R.S. § 39-121.03
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Who can I contact for septic, zoning, or building records?
Please contact Pima County Development Services
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Who can I contact if I have questions about PDEQ Public Records Requests?
Send your questions to firstname.lastname@example.com or
PDEQ at (520) 724-7400
Send your questions to firstname.lastname@example.com or
PDEQ at (520) 724-7400
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