WO2000069411A1

WO2000069411A1 - Use of polymeric adsorbents in pharmaceutical dosage forms

Info

Publication number: WO2000069411A1
Application number: PCT/US2000/009570
Authority: WO
Inventors: Bhagwati P. Kabra; Theron Robert Rodstrom; Janet D. Howie
Original assignee: Alcon Laboratories, Inc.
Priority date: 1999-05-12
Filing date: 2000-04-10
Publication date: 2000-11-23
Also published as: AU4338700A

Abstract

Pharmaceutical compositions containing polymeric adsorbents and methods for their use are disclosed.

Description

IN THE UNITED STATES PATENT AND TRADEMARK OFFICE

USE OF POLYMERIC ADSORBENTS IN PHARMACEUTICAL DOSAGE FORMS

This invention relates to the use of polymeric adsorbents to provide sustained release of a drug (active) and/or to reduce undesired effects of actives. In particular, this invention relates to the use of a polymeric adsorbent in a suspension dosage form where a significant amount of an active is bound to the polymeric adsorbent. Furthermore, this invention relates to ophthalmic compositions for lowering intraocular pressure (IOP) in the treatment of glaucoma.

Background of the Invention

Ion exchange resins have been used to bind drugs in pharmaceutical dosage forms in order to sustain, prolong, or delay the release of the drug. Charged drugs can adsorb/bind on an oppositely charged ion exchange resin. The extent of binding of charged drugs on ion exchange resin depends on various factors including the type and extent of charge on the resin and presence of other competing ions in the formulations.

US Patent No. 2,990,332 (Keating) discloses complexes of cationic drugs with cationic ion exchanger resins. These drug -ion exchange resin complexes offer a way to retard the release of the drug.

The release of a drug from an ion exchange resin is activated by ionic interaction between various body fluids and the drug-resin complex. The rate of release is related to the rate of diffusion of the active ingredient through the resin particle. The particle size and the degree of crosslinking of the resin can alter this rate. The sustained release is influenced by ion exchange equilibrium between the drug-resin complex and the electrolytes in the body fluids. (Brochure: Ion Exchange and Polymeric Adsorption

Technology in Medicine, Nutrition, and the Pharmaceutical Industry, Rohm and Haas. March 1987).

The release of a drug from an ion exchange resin can be further altered by coating the drug-ion exchange resin complex. US Patent No. 4,221 ,778 (Ragunathan) discloses drug-resin complexes coated with a diffusion barrier coating. US Patent No. 4,91 1.920 (Jani et al.) shows that ion exchange resins can be used in ophthalmic formulations to sustain the release of a drug and to reduce the stinging caused by the drug.

US Patent No. 4.931.279 discloses a sustained release polymeric hydrogel dosage form that utilizes an ion exchange resin.

Thus, the current art discloses numerous examples where ion exchange resins alone or in conjunction with a barrier have been used to sustain the release of a drug. In some cases these ion exchange resins have been used to reduce the undesired effect of the active, such as. stinging.

In contrast to ion exchange resins, non-ionic polymeric adsorbents have rarely been used in pharmaceutical formulations, if at all. Martani et al. (WO 96/05864) disclose the use of the polymeric adsorbent XAD 1600 for preparation of a solid pharmaceutical from a liposoluble liquid active substance. The invention by Martani et al. allows for easier preparation of a large number of individual doses from a liquid drug by converting the liquid drug into a solid form by adsorbing it on a polymeric adsorbent. Their invention is directed to convenience of manufacture and use of a large number of individual solid doses compared to individual liquid doses. Their application does not mention that polymeric adsorbents can be used to sustain the release of the drug from the dosage form.

The Brochure by Rohm and Haas discussed above describes application of ion exchange resins in pharmaceutical formulations and also deals with polymeric adsorbents. This brochure discloses the use of polymeric adsorbents in chemical processes for separation or for chemical analysis. It does not mention the use of polymeric adsorbents in pharmaceutical formulations.

Formulations for the treatment of glaucoma are known. Such formulations typically contain an active in combination with suitable preservatives, tonicity agents, pharmaceutical carriers, etc. Of the commonly used activ e drugs, two that are commercially used are beta-blockers and carbonic anhydrase inhibitors. Ideally, such formulations are to be administered topically so that systemic administration uncertainties can be avoided with direct administration to the eye for quicker therapeutic action. The primary objective of this invention is to provide pharmaceutical formulations that use polymeric adsorbents to sustain the release of a drug.

Another objective is to provide ophthalmic formulations that provide for sustained release of a drug.

Another objective of the present invention is to provide formulations that reduce stinging and burning sensations caused by a drug upon instillation in the eye.

Another objective of this invention is to provide ophthalmic formulations that release a drug in response to lysozyme present in the tear fluid.

Another objective of this invention is to provide polymeric adsorbent based formulations that can be preserved with polymeric quaternary ammonium compounds and boric acid.

Another objective of this invention is to provide suspension formulations where aggregation of a polymeric adsorbent is reduced or prevented by using water-soluble polymers that adsorb on the polymeric adsorbent.

Summary of the Invention

This invention is directed to sustained release drug (active) compositions. Sustained release is achieved through the inclusion of a polymeric adsorbent. The adsorbents are aromatic and acrylic resins. The compositions can be liquid suspensions or solids. The invention also includes methods for delivering drugs via compositions comprising at least one drug and a polymeric adsorbent to provide for sustained release of the drug.

Description of Preferred Embodiments

This invention relates to the use of polymeric adsorbents with high surface area in a pharmaceutical formulation or dosage form. A polymeric adsorbent, for the purposes of this invention, is defined as a synthetic polymeric material with a highly porous structure whose internal surfaces can adsorb and desorb a wide variety of different species depending upon the environment in which it is used. The characteristics of the polymeric adsorbents are further described below. The polymeric adsorbents prov ide for sustained release of a drug. Delivery of drugs via dermatological. oral, ophthalmic, nasal, otic, retinal, and vaginal routes are contemplated. The invention is not restricted to solid dosage forms. One of the preferred uses of this invention is in liquid suspensions. The polymeric adsorbent can also be used to reduce undesired effects of drugs such as stinging or burning. It may also be possible to use polymeric adsorbents to improv e the stability of a drug.

The polymeric adsorbents of the present invention adsorb drugs on their surfaces by van der Waals^" forces, such as, hydrophobic bonding, dipole-dipole interaction, and hydrogen bonding in contrast to the adsorption of a drug on ion exchange resins bv ionic interaction. The drug can then be released into the body fluid as described below :

1 . The desorption of a drug in the body fluid is governed by adsorption equilibrium of the drug between the polymeric adsorbent and the body fluid. As the drug from the body fluid is adsorbed by the tissues, more drug is released from the polymeric adsorbent into the body fluid. This is in contrast to the release from ion exchange resins where drug is actively displaced from the ion exchange resin by the electrolytes present in the body fluid.

2. To some extent a drug can also be displaced from the polymeric adsorbent by a species, present in the body fluid, that can adsorb on the polymeric adsorbent, such as. lysozyme, which is present in tears. The extent of release by this mechanism will depend upon the type of adsorbent, drug, and the body fluid. In many cases this active displacement from the polymeric adsorbent may not be as much as in the case of ion exchange resin. This can result in slower release of the drug from a polymeric adsorbent compared to that from an ion exchange resin.

3. The release kinetics of a drug may also depend on the size of the drug particles. They can be further altered by adding an additional barrier, such as. by coating the polymeric adsorbent.

In addition to providing for sustained or slow release, polymeric adsorbents also allow for the use of electrolytes in the formulation without compromising the adsorption of the drug. In many cases the presence of certain electrolytes can enhance the adsorption a of drug to the polymer adsorbent whereas use of an electrolyte in an ion exchange based formulation most probably will reduce adsorption of the drug. Furthermore, polymeric adsorbents can be used to bind ionic as well as non-ionic drugs. Some polymeric adsorbents such as Amberiite XAD16HP. XAD4. and XAD7HP are supplied as fully hydrated insoluble beads of size about 0.3-1.2 mm. In many pharmaceutical applications these adsorbents can not be used as supplied, but require further processing. These processing step can include further purification, drying, and particle size reduction. Amberiite XAD16HP, XAD4. and XAD7 HP can be further purified by washing with water, alcohol, and/or acetone. The particle size of these beads can be reduced by milling in wet or dry state.

Some polymeric adsorbents, e.g., XAD16HP. can be extremelv hydrophobic.

When dried XAD16HP is added to water, it does not wet. Dried adsorbents are generall₎ wetted by first washing with a water miscible organic solvent, such as. acetone or ethanol. However, this method may not be suitable for the preparation of some pharmaceutical dosage forms. It was found that dried polymeric adsorbents such as Amberiite XAD16HP. XAD4, and XAD7 HP could be wetted by adsorbing drug molecules such as levobetaxolol. In order to get good wetting, the amount of levobetaxolol adsorbed needs to be greater than 50% of the adsorption capacity ^r f the resin. The adsorption capacity of a molecule on a given adsorbent can be determined from an adsorption isotherm. It was also found that even a poorly water-soluble drug such as brinzolamide can help in wetting the hydrophobic polymeric adsorbents. Wetting of adsorbents in an aqueous suspension can also be improved by adsorbing water soluble polymers such as hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethylhydroxy ethyl cellulose, poly(vinyl alcohol). poly(ethylene oxide), and poly( vinyl pyrrolidone).

In accordance with the present invention, elimination of feelings of discomfort in ophthalmic applications and elimination of undesirable smells in all contemplated applications can be improved with use of polymeric adsorbents, selected from the group consisting of phenolic, aromatic, and acrylic adsorbent resins. In order to achieve a significant adsorption of a drug the polymeric adsorbents need to have a high surface area, for example, at least 10 square meters/gram (m²/g), preferably 50 m²/g or higher. most preferably 300 m²/g or higher. The preferred resins are commercially available and are sold by Rohm and Haas under the trademark Amberiite® resins. Preferably they are aromatic styrenic adsorbents or acrylate (methacrylate) esters. Of the aromatic and preferable stvrenic adsorbents, those most preferred are styrene-divinv lbenzene copolymers. divinylbenzane polymers, or hydrophilicallv modified styrene- divinylbenzene copolymers. Suitable resins sold under the Rohm and Haas name are identified with the Rohm and Haas product bulletin codes XAD4. XAD 16HP. and

XAD7HP (an acrylate ester.) For descriptions of these, see the generallv av ailable Amberiite® resin brochures of Rohm and Haas, and see U.S. Patent 4.297.220 on uses of Amberiite® polymeric resins. The referenced U.S. patent does not describe use in ophthalmic compositions. For further details of these resins, U.S. Patent 4.297.220 is incorporated herein by reference. Other suitable resins are Oasis HLB, supplied b>

Waters Corporation, and Macronet MN-200 supplied by the Purolite Company.

The amount of the polymeric adsorbent resins should be from about 0.05% bv weight of the composition to about 60% by weight of the composition, preferablv from about 0.25% to about 3.0% by weight of the composition for aqueous suspensions.

Preferably 10% to 50% for solid dosage forms.

It goes without saying that other ingredients which are used, such as, preservatives, buffering agents, tonicity reagents, surface active agents, water soluble polymers, etc. can be added at levels generally ranging from .001 % to about 10% of the topical ophthalmic compositions of the present invention. Useful water soluble polymers include, but are not limited to, HPMC. HEC, EHEC, HPC, Occumer ¹ (Union Carbide). PVA, and also include polyvinyl pyrrolidone (PVP), and PEG. Useful preservatives include but are not limited to quaternary ammonium compounds, such as. BAC and polyquaternium-1 (Polyquad^®).

The preferred topical ophthalmic compositions of the present invention can best be described functionally as having an effective intraocular pressure lowering amount of an active drug or drugs. Examples of active drugs include, but are not limited to. beta- blockers, carbonic inhibitors, prostaglandins, miotics. etc. Generally they will be within the range of from 0.001 % by weight to about 4.0% by weight, preferably from about 0.1% by weight to about 1.0% by weight, and most preferably from about 0.25% by weight to about 0.75% by weight. Where the active drug is a combination of a beta blocker and a carbonic anhydrase inhibitor, the amounts of each should generally be within the ranee of 0.1 to 1.0%. Non-ionic polymeric adsorbents have many uses in oral solid dosage forms across a broad range of drug categories. Non-ionic polymeric adsorbents can be used to delay or slow the release of irritating drugs such as salicylic acid thus reducing irritation. Also, the slow release of compounds from non-ionic polymeric adsorbents mav create sustained activity. Oral solid dosage forms incorporating non-ionic polymeric adsorbents mav also include commonly used tableting excipients such as fillers, disintegrants. binders, glidants. lubricants, color additives and flavorings or flavor modifiers. Oral solid dosage forms incorporating non-ionic polymeric adsorbents may also be coated with commonly used enteric coatings for targeting release in the intestinal tract.

The following examples are offered to further illustrate, but not limit, the scope of the present invention. The formulations set forth in Example 2. 7. 8. and 9 can be dosed 1 - 4 times per day to treat glaucoma and control elevated intraocular pressure according to the routine discretion of a skilled clinician.

Example 1 (Binding of Levobetaxolol to XAD-4)

Formulations given in Table 1 were prepared first by mixing levobetaxolol and XAD-4 in a small amount of water, then all other ingredients were added. The formulations were q.s.ed to 100% with water. They were stirred overnight. The formulations were then autoclaved at 121 °C for 30 minutes.

In order to determine free levobetaxolol, the formulations were filtered through 0.2 micron filters to separate the XAD-4. The concentration of levobetaxolol in filtrate

(free levobetaxolol) was determined using a HPLC method.

The results in Table 1 (Examples 1.1 to 1.5) show that levobetaxolol significantly binds to XAD-4. Furthermore, salts and tonicity agents impact the binding results. The binding is higher in the presence of electrolytes (salts) than in the presence of a non-ionic tonicity agent (mannitol). Also, the binding is higher in the presence of a salt of the multivalent anion (phosphate) than that of the monovalent anion (chloride). Table 1 Composition and Levobetaxolol Binding

Example 2 Binding of Levobetaxolol to Various Polymeric Adsorbents and Ion Exchange

Resins

Formulations of 0.75% levobetaxolol with several polymeric adsorbents and ion exchange resins were prepared. The compositions are given below .

Table 2

Table 2B Composition of 0.75% Levobetaxolol formulation with ion exchange resin

Example 3

Debinding of Levobetaxolol from Various Polymeric Adsorbents in Comparison to the Ion Exchange Resin, Amberiite IRP-69

In this study a given amount of each formulation from Example 2 was mixed overnight with different amounts of artificial tear solution. The mixture was then filtered through a 0.2 micron filter. The amount of drug debound was determined b> analyzing the resin free filtrate. The composition of artificial tear solution with and without lysozvme is given in Table 3. The debinding results are given in Table 4.

Table 3 Composition of Artificial Tear Solution

Table 4 Debinding of Levobetaxolol from Various Adsorbents in Artificial Tear Solution

Levobetaxolol not bound to polymeric adsorbent/resin (% levobetaxolol debound) in artificial tears without Ivsozyme.

Levobetaxolol not bound to polymeric adsorbent/resin (% of Label) in artificial tears with lvsozvme

Example 4 Release of Levobetaxolol from Polymeric Adsorbent, XAD16HP Compared to the

Ion Exchange Resin, Amberiite IRP-69

The composition of levobetaxolol formulations with polymeric adsorbent

Amberiite XAD 16HP and ion exchange resin IRP-69 are given in Tables 5 and 6. The binding of levobetaxolol in these two formulations is similar. The release of levobetaxolol from these formulations was determined using the Controlled Release Analytic System (CRAS) with a suspension cell (Reference: Larry E. Stevens. Paul J. Missel. And John C. Lang, "Drug Release Profiles of Ophthalmic Formulations. 1 .

Instrumentation^", Analytical Chemistry. 1992, 64. pp. 715-723 ). 10 μl of 0.5% levobetaxolol formulation was placed in the suspension cell. The phosphate buffered saline was used as the release medium. The release medium (eluent) was continuously flowing through the cell at rate of 1 μl/min. The eluent from the cell was analyzed for levobetaxolol. The release results given in Table 7 show that release from the polymeric adsorbent is slower than that from the ion exchange resin.

Table 5 Composition of 0.5% Levobetaxolol Formulation With Polymeric Adsorbent,

XAD16HP

Table 6 Composition of 0.5% Levobetaxolol Formulation With Ion Exchange Resin,

Amberiite IRP-69

Table 7

Cumulative Release of Levobetaxolol From Polymeric Adsorbent XAD16HP Based

Formulation Compared to Ion Exchange Resin IRP-69 Based Formulation, as

Determined bv CRAS

Example 5 Effect of Lysozyme on Release from XAD16HP

The release study was carried out using a stirred cell fitted with a 3000 MW cut off membrane. This allows free levobetaxolol to pass through the membrane while preventing polymeric adsorbent from passing. In this study a 4g formulation (Table 8) was mixed with 12g of the artificial tear solution (Table 3) in a 50ml stirred cell for ten minutes. After ten minutes, 12g of solution was expressed through the membrane by applying pressure in the stirred cell. Another 12g of the artificial tear solution was added to the remaining suspension in the stirred cell and mixed for 10 minutes. Again 12g of solution was expressed through the membrane leaving 4 g of the suspension in the cell. Addition of 12g of the artificial tear solution, mixing for ten minutes, and expression of 12g solution were repeated for a total of ten cycles. The expressed solutions were anal zed for the drug concentration to determine the release. The release results are given Table 9. The results show that the presence of lysozyme in artificial tears improves the release of levobetaxolol from XAD16HP.

Table 8 Composition of Formulation

Table 9 Release of Levobetaxolol from XAD16HP in Artificial Tear Solutions With and

Without XAD16HP

Example 6 Release of the Poorh Soluble Drug, Bnnzolamide, From XAD16HP

A. suspension formulation of the poorlv water-soluble drug bnnzolamide was prepared with polymeric adsorbent XAD16HP The composition of this formulation is given in Table 10 The release of bnnzolamide from XAD16HP was studied using the procedure given in Example 5 The release results are given in Table 1 1 The results show that presence of lvsozvme in artificial tears slightlv improv es the release ol the drug

Table 10 Composition of Brinzolamide Formulation With XAD16HP (FID 94921)

Table 11 Release of Brinzolamide from XAD16HP

Example 7 Release of Levobetaxolol and Brinzolamide Combination Formulation from

XAD16HP

The composition of the levobetaxolol/brinzolamide combination formulation is given in Table 12. The release from this formulation in artificial tear solution without lysozyme was studied in a stirred cell using the procedure given in Example 5.

Table 12 Composition of Levobetaxolol Brinzolamide Combination Formulation

From XAD16HP

Table 13 Release of Levobetaxolol and Brinzolamide from XAD16HP

Example 8 Use of Polymers in Formulations to Minimize the Aggregation of Polymeric

Adsorbents

A solution of levobetaxolol, dibasic sodium phosphate, monobasic sodium phosphate, boric acid, EDTA, and polyquaternium-1 was added to adsorbent XAD16HP powder. It was mixed for more than 2 hours. It was autoclaved at 121° C for 30 minutes. In the case of examples 8.2, 8.3. a HPMC or HEC stock solution was added. The formulation was mixed for more than 2 hours. Appearance of XAD16HP in the formulations were observed using a microscope. XAD16HP, had associated significantly in the formulation without water-soluble polymer (example 8.1 ). The association between the adsorbent particles was minimized in formulations with water soluble polymers HPMC and HEC (examples 8.2, 8.3.)

Table 14 Composition of Formulations

Example 9 Preservation of Formulations Containing Non-Ionic Polymeric Adsorbents With

Polyquaternium-1 and Boric Acid

The formulations with polymeric adsorbents XAD4 and XAD16HP are given in Table 15. These formulations were preserved to either EPIB or EPIA standards.

Table 15 Representative Formulation Tested for PET

Table 16 PET Result of the Formulations Given in Table 15

Example 10

Levobetaxolol XAD16HP solid dosage forms. The tablets of 10.1 and 10.2 are useful for treating hypertension. The film of 10.3 is useful as an ocular insert for treating ocular hypertension.

10.1

Compress a mixture containing 40%) Levobetaxolol, 40%> XAD16HP and 20% HPMC to form a tablet.

10.2

Prepare an aqueous slurry containing 3.36% levobetaxolol HC1 and 6% XAD16HP. Dry the slurry to form particles. Mix dried particles with ethyl cellulose 8:2 ratio. Compress to form a tablet.

10.3

Prepare an aqueous slurry containing 3.36% levobetaxolol HC1 and 6% XAD16HP and 2% HPMC. Dry the slurry to form a film. Example 11

Salicylic acid would be lavigated with the non-ionic polymeric adsorbent and a small amount of water to adsorb the drug into the polymer. Starch paste and silica is then mixed into the resulting slurry. This mixture is then granulated and pressed into tablets by methods commonly employed in the art. The tablet is useful as an analgesic.

Example 12

In this example Theophylline and the non-ionic polymeric adsorbent are lavigated together with a small amount of water to absorb the drug into the polymer and the mixture is dried. The remaining ingredients are mixed with the drug-polymer combination and pressed into tablets. The tablets are useful in the control of asthma.

Claims

We Claim:

1. A sustained release composition comprising a pharmaceutically effective amount of an active and a polymeric adsorbent.

2. The composition of Claim 1 wherein the polymeric adsorbent is hydrophobic.

3. The composition of Claim 1 wherein the composition is a dermatological. oral, ophthalmic, nasal, otic, vaginal, or rectal composition.

4. The composition of Claim 3 wherein the composition is a topical ophthalmic composition.

5. The composition of Claim 4 wherein the polymeric adsorbent is selected from the group consisting of phenolic, aromatic, and acrylic adsorbent resins.

6. The composition of Claim 5 wherein the aromatic adsorbent resins are aromatic styrenic resins.

7. The composition of Claim 6 wherein the aromatic styrenic resins are selected from the group consisting of styrene-divinylbenzene copolymers, divinylbenzene polymers, and hydrophically modified styrene divinylbenzene copolymers.

8. The composition of Claim 5 wherein the acrylic adsorbent resins are methacrylate esters.

9. The composition of Claim 1 wherein the concentration of the polymeric adsorbent is from 0.05 weight percent to 60.0 weight percent.

10. The composition of Claim 9 wherein the concentration is from 0.25 weight percent to 3.0 weight percent.

1 1. The composition of Claim 9 wherein the concentration is from 10.0 weight percent to 50.0 weight percent.

12. A method for delivery of an active by administering a composition comprising a pharmaceutically effective amount of an active and a polymeric adsorbent.

13. The method of Claim 12 wherein the composition is administered orall . dermatologically, ophthalmically, nasally, oticly, vaginally, or rectally.

14. The method of Claim 13 wherein the composition is administered ophthalmically.

15. The method of Claim 14 wherein the polymeric adsorbent is selected from the group consisting of aromatic and acrylic adsorbent resins.

16. The method of Claim 15 wherein the aromatic adsorbent resins are aromatic styrenic resins.

17. The method of Claim 16 wherein the aromatic styrenic resins are selected from the group consisting of styrenic-devinylbenzene copolymers, divinylbenzene polymers, and hydrophilically modified divinylbenzene copolymers.

18. The method of Claim 15 wherein the acrylic adsorbent resins are methacrylate esters.

19. The method of Claim 12 wherein the concentration of the polymeric adsorbent is from 0.05 weight percent to 60.0 weight percent.

20. The method of Claim 19 wherein the concentration is from 0.25 weight percent to 3.0 weight percent.

21. The method of Claim 19 wherein the concentration is from 10.0 weight percent to 50.0 weight percent.

22. A sustained release composition comprising a pharmaceutically effective amount of levobetaxolol and a polymeric adsorbent.

23. A method for lowering elevated intraocular pressure by administering a composition comprising a pharmaceutically effective amount of levobetaxolol and a polymeric adsorbent.

24. A sustained release composition comprising a pharmaceutically effective amount of an active and a polymeric adsorbent with a surface area of at least 10m"/g.

25. The composition of Claim 21 wherein the surface area is at least 50m²/g.

26. A method for improving the binding of an active to a polymeric adsorbent which comprises adding a salt of a divalent anion to a composition comprising a pharmaceutically effective amount of an active and a polymeric adsorbent.