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Title:  Spray-drying process for the preparation of microparticles

United States Patent:  6,451,349

Issued:  September 17, 2002

Inventors:  Robinson; Stuart (Melton Mowbray, GB); Smith; Susan Stewart (Leicestershire, GB)

Assignee:  Quadrant Healthcare (UK) Limited (Nottingham, GB)

Appl. No.:  342356

Filed:  June 29, 1999

Abstract

Microparticles, obtainable by spray-drying a substantially pure solution of a therapeutic agent, consist essentially of the agent having its therapeutic activity when administered to the lung. In a preferred embodiment the agent is insulin.

DESCRIPTION OF THE INVENTION

Microparticles of the invention "consist essentially" of the therapeutic agent. This term is used herein to indicate that they are substantially free of polysaccharide, or buffer salt, e g citrate, since none is necessary. In general, there will be no polysaccharide present at all, although an amount of up to, say 10% by weight may be tolerated. The absence of polysaccharide has the advantage that a given unit dosage, e.g. a particle, contains essentially only the intended active component. This is an important consideration, for a drug that may be required in large amounts. Another advantage is the avoidance of delivering unnecessary material to a subject. A further advantage is that consistent dosing of the therapeutic agent is facilitated, this is especially important where there is a narrow therapeutic window.

The absence of buffer salt is desirable as it allows a more concentrated feedstock solution of the active agent to be spray-dried resulting in significant cost savings and providing a more commercial-scale process to be adopted.

The term "substantially pure" is used herein to indicate that the feedstock solution to be spray-dried comprises primarily only therapeutic agent and solvent. Again, as described above, there may be minor amount of solids other than the active agent, but this has no significant effect on the eventual stability of the product.

Insulin microparticles of the invention may include components that are produced during the successive addition of acid and alkali, in preparation of the feedstock, e.g. a salt. For example, NaCl is formed if the acid and alkali are respectively HCl and NaOH. It has been found that the presence of NaCl apparently has no stabilising effect. Indeed, stability may be greater with reduced amounts of salt, again allowing a more concentrated feedstock to be used.

Typically, the solution for spray-drying may contain less than 4% by weight of salt, by weight of total solids. The salt content is based on theoretical considerations, by titration to pH 7. More particularly, this value is calculated by consideration of the molar quantities of the ions added during dissolution. The solution may contain any desired amount of the therapeutic agent, e.g. more than 20, 30 or 50 mg/ml, often up to 100 or 200 mg/ml.

As indicated above, successive addition of acid and alkali apparently destroys the crystalline form of Zn insulin. Zn may dissociate from the hexameric complex but need not be removed. Accordingly, Zn may be present in the microparticles. If desired, this or any other component, other than the therapeutic agent, may be removed, using any suitable technique known to those of skill in the art. In a preferred embodiment for insulin, the Zn is removed from solution prior to spray-drying. This may be achieved by diafiltering the solution according to methods known in the art. The Zn-free insulin may have greater stability than the Zn-containing product. Moisture may also be present.

As disclosed in more detail in WO-A-9218164, WO-A-9408627 and other Andaris publications, the conditions of spray-drying can be controlled so that microparticles having a defined size range, e.g. 0.1 to 50 .mu.m, can be obtained. The mass median particle size is preferably 1 to 10 .mu.m, when the product is intended for administration by inhalation.

The microparticles (microcapsules) obtained by spray-drying may be solid or hollow Further, the surface may be smooth or "dimpled"; a dimpled surface may be beneficial for inhalation.

The microparticles have good stability and may be maintained as such, i.e. as a dry powder, in a container. During storage or in formulation, they may be mixed with any suitable pharmaceutical agents, carriers, bulking agents etc, and they may be processed by any technique desired to give a product having the properties intended for the ultimate therapeutic use. In particular, the formulation of particles for formulations that can be delivered to the lung, e.g. using a metered dose or dry powder inhaler, are known to those skilled in the art.

The nature of the container is not critical. For example, it may be a glass jar or plastics box. It merely defines a storage environment within which, unlike the prior art and as evidenced below, there is no need to remove moisture or otherwise to control the conditions.

The therapeutic agent may be any protein or peptide having a desired therapeutic effect. Included within the definition of proteins and peptides are functional derivatives, such as glycoproteins. Typical examples of proteins that may be used include enzymes, hormones and blood plasma products. DNase and trypsin are specific examples. Others include growth hormone, calcitonins, interferons, interleukin-1 receptor and low molecular weight heparin.

The therapeutic agent may in particular be any of those described in WO-A-9632149. Insulin that is used in the invention may be of any suitable form. It may be, for example, bovine or human insulin. Results that have been obtained, regarding the stability of bovine insulin, apparently apply also to human insulin.

Claim 1 of 7 Claims

What is claimed is:

1. A process for the preparation of microparticles, which comprises spray-drying a substantially pure solution of a therapeutic agent to form microparticles that consist essentially of the therapeutic agent having therapeutic activity when administered to the lung, wherein the agent is insulin and wherein the method comprises:

providing a solution comprising Zn-insulin dissolved in acid;

adding alkali to the solution to produce a pH of the solution greater than 7; and

spray drying the solution to form the microparticles.
 


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