WO2002060486A2

WO2002060486A2 - Controlled release microsphere system for administration of drug to the eye

Info

Publication number: WO2002060486A2
Application number: PCT/CA2002/000086
Authority: WO
Inventors: Bernard B. Fresco
Original assignee: Fresco Bernard B
Priority date: 2001-01-29
Filing date: 2002-01-29
Publication date: 2002-08-08
Also published as: AU2002229434A1; WO2002060486A3

Abstract

A device and method for using microspheres containing a neutralizing agent to automatically stop a chemical reaction after a selected period of time, or after a selected result has occurred. A particular application is for the treatment of glaucoma, wherein the treatment involves the administering of collagenase to the limbus of the eye, and the microspheres contain EDTA which is automatically released into the collagenase after a selected period of time, neutralizing the collagenase.

Description

Title: Method and Apparatus for Administering Drugs to an Organism

FIELD OF THE INVENTION

The present invention concerns a method and apparatus for controlling a chemical reaction caused by the administration of a chemical compound to an organism. More particularly, this invention is concerned with controlling the administration of drugs to the eye, and more particularly to controlling the reaction time of administered drugs to the eye.

BACKGROUND OF THE INVENTION

It is generally preferable to administer the minimum amount possible of a drug to a patient, in order to minimize the risks of side effects, while still ensuring that enough of the drug has been administered to produce the desired result. Depending on the method by which the drug is introduced to the patient, this may translate into a drug being administered at the lowest possible dosage, or it may mean that a drug will be administered for a minimum amount of time.

When administering drugs to the eye, there are few ways of ensuring that the minimum effective amount of the drug has been administered. One way is to administer a specific dosage of the drug, and then manually examine the eye to verify the results.

Another way is to administer the drug for a specified period of time, and then manually remove the administration device. Such a method is disclosed in U.S. Patent No. 5,462,739 (Dan et al.). Dan et al. teaches a device and method for pinpoint delivery of pharmacological compositions to the outer hard coat of the eye, and particularly for pinpoint application of collagenase to the limbus for the treatment of glaucoma. As taught by Dan et al., a specified quantity of collagenase, is applied using a device at a specific, pinpoint location on the limbus. The collagenase degrades the collagen structures in the limbus, thereby forming a pinpoint hole into the anterior chamber of the eye, releasing aqueous from the anterior chamber, and reducing pressure in the eye. Dan et al. teaches that the degradation of the collagen structures by the collagenase occurs preferably only for a specified period of time, after which the administration device is removed manually from the eye and the eye is then flushed with a solution of calcium chelator ethylenediaminetetraacetic acid, hereinafter referred to as calcium chelator EDTA. There is a continuing need for a simple but effective device and method that could be used to automatically stop the administration of a drug to the eye after a specified period of time, or after a specified result has been achieved.

SUMMARY OF THE INVENTION

The present invention is directed to microspheres for use in automatically controlling a chemical reaction, and particularly, the administration of a pharmacological composition to the eye, wherein each microsphere comprises a wall that is degradable by the composition, and a neutralizing agent, that neutralizes the composition, stopping the administration of the composition to the eye. The thickness and chemical formula of the wall are selected to expose the neutralizing agent to the composition after a selected period of time.

In a first aspect of the present invention, there is provided a system of microspheres each of said microspheres comprising: a compound adapted for altering a chemical reaction caused by the administration of a chemical composition to an organism; and a wall, said wall enclosing said compound, and said wall being degradable by at least one chemical present during said chemical reaction. The compound can alter the reaction by stopping the reaction or slowing the reaction, by reaction with one or more of the chemicals present. Further, the compound can react with at least one chemical present to change the nature of the reaction or initiate a second, different reaction.

The microspheres can also contain one or more additional compounds to creating the desired reaction scheme. For example, one compound would stop the first reaction, as detailed above, and a second compound could then start a second chemical reaction. Further, the invention contemplates the use of embedded, slow release systems. For example, a chemical reaction would be controlled in any of the ways outlined above. For example, the relevant compound or compounds could be encased in a hyaluronic polymer, which are known for controlled, slow release drug systems.

In another aspect, the invention is directed to an insert that contains microspheres for use with a microcontainer of a pharmacological composition for administration to the eye. The insert is removably insertable into the microcontainer. The microspheres are the same as those described above, and therefore stop the administration of the composition after a selected period of time, by neutralizing the composition.

In another aspect, the invention is directed to a method of administering a pharmacological composition to a body to obtain a reaction between the pharmacological composition and the body, and controlling the reaction time, the method comprising:

(a) applying a pharmacological composition selected to react with the body;

(b) providing microspheres comprising a wall that is degraded by at least one chemical present during the reaction of the pharmacological composition with the body and, contained by the wall, a neutralizing agent for neutralizing the pharmacological composition;

(c) applying the microspheres and the pharmacological composition simultaneously to the body, whereby after a selected period of time the walls of the microspheres degrade to release the neutralizing agent, to neutralize the pharmacological composition and to terminate the reaction of the pharmacological composition with the body.

In yet another aspect, the invention is directed to a system of microspheres, including first and second microspheres. Each of the first microspheres includes a chemical composition for administering to an organism and for causing a chemical reaction within the organism. Each of the first microspheres includes a wall that encloses the chemical composition, and is permeable to the chemical composition at a selected rate. Each of the second microspheres includes a compound adapted for altering a chemical reaction caused by the administration of the chemical composition to the organism. Each of the second microspheres includes a wall that encloses the compound, and is degradable by at least one chemical present during the chemical reaction.

In yet another aspect, the invention is directed to a system for administering a chemical composition to a target site in an organism, including a chemical composition for administration to the target site, a system of microspheres and a housing. Each of the microspheres includes a compound adapted for altering a chemical reaction caused by the administration of the chemical composition to the organism. Each of the microspheres includes a wall that encloses the compound, and is degradable by at least one chemical present during the chemical reaction. The housing encloses the chemical composition and the microspheres together in a cavity. The housing is permeable to the chemical composition at a selected rate.

DESCRIPTION OF THE DRAWINGS

The present invention will now be described by way of example only, with reference to the following drawings, in which:

Figure 1 is a view of a system of microspheres in accordance with a first embodiment of the present invention, with a sectional side view of a single microsphere;

Figure 2 is a sectional side elevation view of a known application device for applying a pharmacological composition to the eye;

Figure 3 is an isometric view of a device in accordance with the present invention, for use with the application device of Figure 2; Figure 4 is a view of a system of microspheres in accordance with an alternative embodiment of the present invention, with a sectional side views of microsphere of each different type; Figure 5 is a perspective view of a system for delivering a composition to a target site in an organism in accordance with another alternative embodiment of the present invention; and

Figure 6 is a sectional side view of the device shown in Figure 5, taken along section line 6-6.

DETAILED DESCRIPTION OF THE INVENTION

Reference is first made to Fig. 1 , which illustrates a system of microspheres 10 made in accordance with a first preferred embodiment of the present invention and which will be used for the purposes of describing the operational aspects of the invention.

When a chemical reaction is made to occur, the present invention provides for the addition of a quantity of the microspheres 10, so that the added microspheres 10 serve to stop the chemical reaction from continuing after a predetermined period of time. For example, when administering a pharmacological composition to the eye, a quantity of microspheres 10 can be included in the composition, such that, after a specified period of time, the microspheres 10 release a neutralizing agent to stop the further administration of the composition to the eye, the neutralizing agent neutralizing the active drug or drugs in the composition.

In order to accomplish this, each microsphere 10 comprises a generally spherical wall 12, which encloses a generally spherical cavity 14, which holds a neutralizing agent 16. Wall 12 is made from a material that is selected to be degradable by the composition being administered to the eye. For example, when using a composition of collagenase on the eye, wall 12 can be made from cross-linked collagen, or collagen gelatin.

The thickness "t" and the chemical formula of wall 12 are selected based on the length of time desired for the chemical reaction to occur. If it is desired for the active drug to act on the eye for a relatively long period of time, a relatively thick wall 12 and/or a relatively slow-to-degrade wall material may be selected, so that it takes longer for wall 12 to be degraded. Conversely, if a short period of time is desired, a relatively thin wall 12 and/or relatively chemically active wall material may be selected, so that it takes less time for wall 12 to be degraded.

Diameter 'd' of microspheres 10 is selected based on the specific application, and may depend on the wall thickness 't'. If a specific quantity of neutralizing agent 16 is required per microsphere, then the volume of cavity 14 is determined by the quantity of neutralizing agent required, and therefore the diameter 'd' of the microsphere 10 depends on the wall thickness selected for the specific application.

Once wall 12 has degraded sufficiently, interior cavity 14 and neutralizing agent 16 are exposed to the composition. Neutralizing agent 16 is selected to react with and neutralizes or otherwise stops the pharmacological composition, preventing further administration of the composition on the eye. In the case where collagenase is administered on the eye for the treatment of glaucoma, for example, neutralizing agent 16 is preferably a solution of calcium chelator EDTA. A sufficient quantity of neutralizing agent 16 must be contained within microspheres 10, such that all of the active drug or drugs in the pharmacological composition are neutralized, and that no residual amount of active drug in the composition continues to act on the eye. An advantage of using microspheres is that the neutralizing agent is present, in numerous small amounts, uniformly distributed throughout the composition, so that no mixing is required.

Both wall 12 and neutralizing agent 16 may also be designed to meet other criteria. For example, for use in the eye, wall 12 and neutralizing agent 16 must also be selected to be biologically compatible with the eye. Preferably, both wall 12 and neutralizing agent 16 are biodegradable and/or resorbable in the body once their function has been performed. Further, neutralizing agent 14 is preferably selected to be pH compatible with the eye, and would therefore have a pH of approximately 7.4. Reference is now made to Fig. 2, which shows an application device 20, as disclosed in U. S. Patent No. 5,462,739 (Dan et al.), for the administering of a pharmacological composition to a pinpoint location on the hard outer coat of the eye. The contents of U.S. Patent 5,462,739 are hereby incorporated by reference. Often, a device, such as a syringe, or one of the devices disclosed by Dan et al. Is used to aid in administering a drug or pharmacological composition to the eye. When devices such as device 20 are employed, it may occur that the pharmacological composition be stored in device 20 for an unspecified period of time, perhaps several hours, before the drug is administered. If it is desired that microspheres 10 be employed as described above to stop the administration of the drug to the eye, it will often be desirable that microspheres 10 not be in contact with the composition until the composition is administered to the eye, so that the release of neutralizing agent 16 only occurs after the composition has acted on the eye for the desired period of time. Where possible, it is preferable to introduce the microspheres into the device when the device is about to be used to administer the drug, while ensuring even distribution of the microspheres.

Some devices, however, such as device 20, shown in Figure 2, and disclosed by Dan et al., include means for sealing the pharmacological composition in the device, until such time as the composition is to be administered to the eye. Device 20 includes an administering piece 22 and an introducer 24. Administering piece 22 is generally disk shaped and includes an integrally formed microcontainer 26, which holds the drug to be administered. Introducer 24 holds administering piece 22 and is used to help position administering piece 22 on the eye. Introducer 24 includes a shield surface 28 which serves to seal microcontainer 26 until the administering piece 22 is positioned on the eye. As well, a chamber 30 is formed when administering piece 22 is in place on introducer 24. Chamber 30 is used to contain adhesive, which will affix administering piece 22 to the eye.

To use device 20, as disclosed by Dan et al., administering piece 22 is oriented so that microcontainer 26 is upright, and a quantity of a pharmacological composition is placed inside microcontainer 26. A quantity of adhesive, such as medical glue is then placed on surface 32 of piece 22, and introducer 24 is placed on top of piece 22, so that shield surface 28 seals microcontainer 26, and so that piece 22 is well seated on seating portion 34. The assembly is then inverted so that microcontainer 26 is open-face-down, as shown in Figure 3. Device 20 is then used to administer the pharmacological composition using the following method. Device 20 is held in place adjacent the point to be treated, and the introducer 24 is removed while pressure is applied to depression 36 on dorsal surface 38, thereby removing introducer 24 from under piece 22. Piece 22 at this point is in position on the surface of the eye, so that microcontainer 26 is open-face-down at the point on the limbus to be treated, and the adhesive is in contact with the surface of the body, holding piece 22 in place.

Once piece 22 is in place on the limbus of the eye, the pharmacological composition in microcontainer 26 acts on the pinpoint location of the limbus, covered by microcontainer 26. For the treatment of glaucoma, for example, the pharmacological composition may contain collagenase which breaks down the collagen structure in the limbus. By using device 20, the collagenase will form a cone shaped hole into the anterior chamber of the eye, releasing aqueous, and thereby reducing the pressure in the eye.

Reference is now made to Figure 3, which shows an insert device 40 in accordance with the present invention, for use with the application device shown in Figure 2. Since it is important to keep the microspheres 10 separate from the pharmacological composition until it is desired that they are exposed to each other, insert 40 may be employed to seal microspheres 10 from the composition, within microcontainer 26.

Insert 40 comprises a microcontainer 42 for containing microspheres 10, a locking means 44, a sealing surface 46, a push-down surface 47 and a removal tab 48. Insert 40 can be removably inserted into microcontainer 26, such that microspheres 10 are stored in microcontainer 42 of insert 40, and the pharmacological composition is stored in the remaining volume of microcontainer 26. In order to accomplish this, microspheres 10 must be introduced into microcontainer 42; then insert 40 is to be inserted, into microcontainer 26, with sealing surface 46 in contact with the bottom of microcontainer 26; and then the pharmacological composition is to be introduced into the remaining volume of microcontainer 26. Note that tab 48 is configured to leave an opening for filling the remaining volume of microcontainer 26, after the insert 40 has been placed into the microcontainer 26. Locking means 44 maintains device 40 in a constant upright orientation when device 40 is in place in microcontainer 26, in order to help seal the contents of microcontainer 42 from the contents of the microcontainer 26. Because microcontainer 26 is disclosed by Dan et al. to be generally in the shape of a right cylinder in a particular embodiment, locking means 44 may comprise a partial right cylindrical form such that, circumferentially, the locking means 44 includes more than a 180° of a right cylinder, and therefore has a supra-semi-cylindrical contour face. Alternatively, locking means 44, may be any form or shape that serves to maintain device 40 in a specific orientation when inserted into microcontainer 26. As well, in order to seal the contents of microcontainer 42, sealing surface 46 is smooth and contacts the bottom of microcontainer 26 uniformly, so as to inhibit leakage into or out of microcontainer 42. Push- down surface 47 simultaneously contacts shield 28, thereby helping to clamp device 40 in position in microcontainer 26. Device 40 must be sized such that, when device 40 is inserted into microcontainer 26, shield 28 can still contact and seal microcontainer 26. Device 40 can be removed from microcontainer 26 by means of removal tab 48. Just before the application of administering piece 22 to the eye, device 20 is inverted and piece 22 is temporarily removed from introducer 24. Insert 40 is then removed from microcontainer 26 so that microspheres 10 remain in microcontainer 26, and mix with the pharmacological composition in microcontainer 26. Piece 22 is then re- placed onto introducer 24, and the assembly is inverted again for positioning on the limbus of the eye. Alternatively, the microspheres can be stored separately, and when required, a suitable quantity of them can be injected into microcontainer 26, so as not to use insert 40.

For the treatment of glaucoma, in order to use microspheres 10 of the present invention to automatically stop the administering of collagenase to the limbus of the eye using a device and method as disclosed by Dan et al, it is preferable to determine the length of time required for the collagenase to penetrate into the anterior chamber of the eye and release aqueous. In order to determine the length of time required, the scleral thickness may be measured, by means of an ultrasonic device, as is known in the art. From the thickness of the sclera, the reaction time can then be calculated, and microspheres 10 with the appropriate wall thickness 't' or the appropriate wall composition can be selected to be inserted into the collagenase composition. For microspheres that are used in applications within the human body, biocompatibility is very important, so as to minimize immune response, and to avoid thrombolytic consequence. Hence there is a need to minimize platelet activity. In order to enhance biocompatibility in blood, microspheres 10 may further include a coating of albumin, as albumin is non-antigenic, and biodegradable.

Microspheres 10 with collagen walls 12 and containing EDTA as the neutralizing agent 16, may be manufactured by the following method. An aqueous solution of collagen and EDTA is first formed. The pH of the solution may be controlled, preferably by adding an alpha-hydroxy acid. The addition of the acid to the solution aids in the stability of the microspheres that are formed by this method. In an emulsification step, the aqueous solution is then added to an immiscible liquid or oil phase, and the resulting droplets of collagen and EDTA are then dispersed by high speed stirring, forming a suspension. Stabilization of the suspended droplets, to form microspheres 10 is brought about by heating the suspension. Alternatively to heating the suspension, chemical cross-linking may be employed to stabilize the droplets and form microspheres 10, using a cross-linking agent, such as glutaraldehyde. Alternatively, stabilization of the suspension of droplets may be made to occur by subjecting the droplets of ultraviolet radiation. When using ultraviolet radiation, however, the liquid in which the droplets are suspended must be substantially ultraviolet transparent. Alternatively, ultraviolet radiation may be used to cause the polymerization of certain chemical components of microspheres 10 in the suspension, in the aqueous solution, or in the stabilized microsphere itself.

Proteins used in the production of microspheres 10 may be modified proteins. Proteins may be modified at any stage, in the aqueous solution, in the suspension, or in the stabilized microsphere 10.

Tannic acid may be used in the cross-linking step of manufacture. If tannic acid is used in this step, the resulting anti-enzyme activity caused by the microspheres is affected and must be considered for the specific application. A number of methods may be used to separate microspheres

10 from the solution, including evaporation of the solvent, centrifuging or other mechanical phase separation means, and spray drying.

While an insert, such as insert 40 may be made from a number of materials, such as titanium or a biocompatible polymer, it is alternatively possible that an insert may be made from a material that is itself selected to degrade as a result of the composition in microcontainer 26, similarly to the walls 12 of the microspheres 10 themselves. Such an insert would therefore not require a removal tab 48, and furthermore, the insert could be completely sealed, thus facilitating the insert's placement in microcontainer 26. Furthermore, such an insert may be configured in size and shape for use with other application devices for introducing pharmacological compositions to other parts of the human body, or to other organisms. Because such an insert would be degraded by the pharmacological composition, the insert would preferably be placed in microcontainer 26 immediately before the composition is administered.

Microspheres 10 may be made to be pH-sensitive, such that they will release neutralizing agent 16 upon exposure to an environment greater than, or alternatively, less than a specified pH. For example, for the treatment of glaucoma, the microspheres can be made to release neutralizing agent 16 upon exposure to a pH of 7.4 or greater. Thus, the microspheres can have a wall that is stable at one pH, but when exposed to a solution having a pH of 7.4, may degrade at a known rate until the neutralizing agent within the microspheres is released. These microspheres 10, added to a collagenase composition and administered to the limbus of the eye, would be exposed to the aqueous, once the collagenase has penetrated into the anterior chamber of the eye. The exposure to the aqueous, which possesses a pH of about 7.4, would then cause microspheres 10 to release neutralizing agent 16, neutralizing and stopping the further administration of the collagenase. Making microspheres 10 pH-sensitive, can be used as an alternative method of making microspheres 10 release neutralizing agent 16. If microspheres 10 are made to be pH-sensitive, they do not require walls 12 to be made from a substance that is degradable by a component of the pharmacological composition. In this way, microspheres 10 are adapted to release neutralizing agent 16 automatically at the correct moment, (ie. when they are exposed to aqueous from the eye, indicating therefore that the collagenase has penetrated into the anterior chamber), regardless of the exact length of time required for the penetration to occur. Alternatively, microspheres 10 may be made to be both pH-sensitive and to have walls 12 that are degradable by a component of the pharmacological composition. PH- sensitive or insensitive microspheres may be made by selecting polyglycerol esters.

Microspheres 10 of different levels of pH-sensitivity, of different chemical components, containing different neutralizing agents 16, and of different diameters and wall thicknesses may be employed in a single pharmacological composition, in order to selectively neutralize specific components of the composition after different periods of time.

When using microspheres on the eye, the anionicity or cationicity of the microspheres can influence the body's response to them, however a pH of above 5 is optimal to prevent neutralization of charge and resulting in aggregation.

While microspheres have been shown to be used for inhibiting the prescription of a composition on the eye, they can alternatively be used to inhibit the administering of pharmacological compositions to other parts of the human or animal body, or furthermore, to other organisms.

Reference is made to Figure 4, which shows a system 50 of first microspheres 52 and second microspheres 10, in accordance with an alternative embodiment of the present invention. System 50 can be used to release a pharmacological composition 54 into a target site in the body of a human or other organism, on a time-release basis, and then stop the reaction between the composition at the site after a selected period of time.

The first microspheres 52 have a generally spherical wall 56, surrounding a generally spherical cavity 58. Inside the cavity 56 is the pharmacological composition 54. The first microspheres 52 may be made by any suitable means. For example, the first microspheres 52 may be made as disclosed in US Patent No. 6,228,423 (Sokoll et al.), which is hereby incorporated by reference. As mentioned in that patent, the first microspheres 52 can provide a wall defining a cavity encapsulating the compound or the microspheres can be essentially homogenous, i.e. without a distinct cavity and with the compound then distributed through the wall.

The wall 56 may be made from a biocompatible polymer, which may also be biodegradable. The wall 56 may have any suitable selected permeability to the composition 54, so that the composition 54 is released at the target site at a selected rate, and is thus, time-released. In embodiments where the wall 56 is biodegradable, the wall 56 may be selected to biodegrade after the release of all of the composition 54, so that any amount of the composition 54 can be provided within the cavity 56 for release in a time-controlled manner in the composition 50, before the microspheres 10 stop the reaction. After a selected period of time, or alternatively at a selected point in the reaction of microspheres 52 at the target site, i.e. when a particular reaction product is formed, microspheres 10 break down and release the neutralizing agent 16 to stop the reaction. The breakdown of the microspheres 10 may be as a result of the composition 54. Alternatively, microspheres 10 may be biodegradable and may therefore break down from reaction with body chemicals present at the target site.

The neutralizing agent 16 is then selected to neutralize any of composition 54 that is present outside of microspheres 52. As a further alternative, neutralizing agent 16 may be selected to also initiate or to escalate and complete the breakdown of walls 56 of microspheres 52, so that any remaining composition 54 present inside microspheres 52 is also released and thus neutralized relatively quickly. For this purpose, the agent 16 can be a two component system; one component would be a neutralizing agent for the composition 54 and the other component could be a solvent for the walls 56 or other agent that breaks down the walls 56.

It will in general be realized that various combinations can be provided, to achieve different reaction schemes. For example, other microspheres could be present to initiate a second reaction with a desired part of the body or organism, once the first reaction described above has been terminated. For this purpose, additional compounds or compositions can be provided within one or both of the first and second microspheres 16, 54. Alternatively, where there is incompatibility between the various compositions, one or more other microspheres can be provided, each additional group of microspheres corresponding to one of the microspheres 16, 52 in basic structure.

Reference is now made to Figures 5 and 6, which show a system 60 including a pharmacological composition 62, microspheres 10 and an implantable device 64 for delivering composition 62 in a time- controlled manner to a specific portion of the body of an organism, which avoids the need to provide two different types of microspheres. Device 64 may be the device described in US Patent No.

6,001 ,386 (Ashton et al.), which is hereby incorporated by reference. The device 64 may include a polymer housing 66, which encloses a cavity 68.

The pharmacological composition 62 and the microspheres 10 are stored in the cavity 68.

The housing 66 may be made from a suitable biocompatible polymer that has a selected permeablility to composition 62. Housing 66 may be non-biodegradable.

Housing 66 may be positioned at the target site by any suitable means. For example, housing 66 may include a peripheral flange 70 in which is embedded a support ring 72. The support ring 72 may be made from a suitable tear-resistant material, such as a biocompatible metal. The device 64 may then be surgically inserted into or attached at any suitable point in an organism, for example, in the vitreous of the eye. The device 64 may be sutured at the selected target site by routing the suture through the flange 70 inside the support ring 72. Care should be taken to ensure that the suture does not puncture the cavity 68 so that composition 62 is not inadvertently released at an uncontrolled rate. The device 64 may then release composition 62 in a time-controlled manner for a selected period of time.

The housing 66 may be made to be permeable to chemicals (or at least one chemical) in the body that are present at the target site during reaction with the composition, so that these chemicals enter the cavity 68. The microspheres 10 are made to degrade in the presence of these chemicals, so that after a selected period of time, the microspheres 10 break down and neutralize any remaining amount of composition 62 in the cavity 68. Alternatively, the microspheres 10 can be caused to break down by some other chemical present during the reaction, for example, a reaction product, but this presents the problem of how this chemical is generated and/or becomes present during the reaction.

As will be apparent to persons skilled in the art, various modifications and adaptations of the systems and methods described above are possible without departure from the present invention, the scope of which is defined in the appended claims.

Claims

I CLAIM:

1. A system of microspheres, each of said microspheres comprising: a compound adapted for altering a chemical reaction caused by the administration of a chemical composition to an organism; and a wall, said wall enclosing said compound, and said wall being degradable by at least one chemical present during said chemical reaction.

2. A system as in claim 1, wherein said wall has a thickness and a chemical composition, said thickness and said chemical composition having been selected to expose said compound to said chemical reaction after a selected period of time.

3. A system as in claim 1 , for use with a collagenase composition, wherein said compound is selected to neutralize said collagenase composition.

4. A system as in claim 3, wherein said wall is made from a collagen-based material.

5. A system as in claim 3, wherein said neutralizing agent is a solution of calcium chelator EDTA.

6. A system as in claim 3 for use with the eye, wherein said neutralizing agent has a pH that is compatible with the aqueous.

7. A system as in claim 6, wherein said neutralizing agent has a pH substantially equal to 7.4.

8. A system as in claim 1 , wherein said wall is selected to be stable in a first pH environment and to be degradable in a second pH environment.

9. A system as claimed in claim 1 , wherein said compound is selected to stop the chemical reaction.

10. A system as claimed in claim 9, which includes a second compound for initiating a second chemical reaction.

11. An apparatus for use with an application device for applying a pharmacological composition to the eye, said application device including an administration piece and an introducer, said administration piece including a first microcontainer for containing said pharmacological composition and having an open top and a closed bottom, said introducer comprising a shield for pressing against said open top and sealing said first microcontainer, said apparatus comprising: an insert for containing microspheres and for insertion into said microcontainer, said insert including: a microsphere microcontainer, said microsphere microcontainer containing said microspheres; a sealing surface around said microsphere microcontainer, said sealing surface being adapted to continuously contact said closed bottom of said first microcontainer to seal said microsphere microcontainer from said pharmacological composition; a locking means for maintaining said insert in a specific orientation; and a push-down surface being adapted to be in contact with said shield, simultaneously as said sealing surface is in contact with said closed bottom; wherein said microspheres have a wall that is degradable by said pharmacological composition, and a neutralizing agent contained by said wall, said neutralizing agent being adapted to neutralize said pharmacological composition.

12. A system as in claim 11, wherein said wall has a thickness and a chemical composition, said thickness and said chemical composition being selected to expose said neutralizing agent to said pharmacological composition after a selected period of time.

13. An apparatus as in claim 12, wherein said pharmacological composition comprises a collagenase composition.

14. An apparatus as in claim 13, wherein said wall is made from a collagen-based material.

15. An apparatus as in claim 14, wherein said neutralizing agent is a solution of calcium chelator EDTA.

16. An apparatus as in claim 11 , wherein said neutralizing agent has a pH that is compatible with the aqueous of a human eye.

17. An apparatus as in claim 11 , wherein said neutralizing agent has a pH substantially equal to 7.4.

18. An apparatus as in claim 11 , wherein said insert includes a removal tab.

19. An apparatus as in claim 11 , wherein said locking means comprises a supra-semi-cylindrical contour face.

20. An apparatus as in claim 11 , wherein said wall is selected to be stable in a first pH environment and to be degradable in a second pH environment.

21. A method of administering a pharmacological composition to a body to obtain a reaction between the pharmacological composition and the body, and controlling the reaction time, the method comprising:

(a) applying a pharmacological composition selected to react with the body; (b) providing microspheres comprising a wall that is degraded by at least one chemical present during the reaction of the pharmacological composition with the body and, contained by the wall, a neutralizing agent for neutralizing the pharmacological composition; (c) applying the microspheres and the pharmacological composition simultaneously to the body, whereby after a selected period of time the walls of the microspheres degrade to release the neutralizing agent, to neutralize the pharmacological composition and to terminate the reaction of the pharmacological composition with the body.

22. A method as in claim 21 , wherein the pharmacological composition and the microspheres are applied to the surface of the body.

23. A method as in claim 21 , wherein the pharmacological composition and the microspheres are applied to the eye.

24. A method as in claim 21 , further comprising the step of storing the microspheres separately from the pharmacological composition and mixing the microspheres and the pharmacological composition together immediately prior to step (c), and then applying the mixture to the body.

5. A system of microspheres, comprising: a plurality of first microspheres, each of said first microspheres including a chemical composition for administering to an organism and for causing a chemical reaction within said organism, and each of said first microspheres including a wall, said wall of said first microsphere enclosing said chemical composition, and being permeable to said chemical composition at a selected rate; and a plurality of second microspheres, each of said second microspheres including a compound adapted for altering a chemical reaction caused by the administration of said chemical composition to said organism, and each of said second microspheres including a wall, said wall of said second microspheres enclosing said compound, and being degradable by at least one chemical present during said chemical reaction.

26. A system as claimed in claim 25, wherein each of the second microspheres defines a cavity for the compound, and the wall thereof encapsulates the compound.

27. A system as claimed in claim 25, wherein each of the second microspheres has the wall extending substantially across the entire microsphere and has the compound uniformly dispersed through the wall thereof.

28. A system for administering a chemical composition to a target site in an organism, comprising: a housing defining a cavity; a chemical composition within said cavity for administration to said target site; and a plurality of microspheres within said cavity, each of said microspheres including a compound adapted for altering a chemical reaction with an organism caused by the administration of a chemical composition to an organism, and each of said microspheres including a wall, said wall enclosing said compound, and said wall being degradable by at least one chemical present within said cavity during said chemical reaction, wherein said housing being permeable to said chemical composition at least at a selected rate.

29. A system as claimed in claim 28, wherein said housing is permeable to at least one chemical present during reaction of said chemical composition with the organism, and wherein said walls of said microspheres are degradable by said at least one chemical.

30. A system as claimed in claim 28, wherein said at least one chemical is present outside said housing and housing is permeable to said at least one chemical.