Link:  Pharm/Biotech Resources

Title:  Formulation for inhalation

United States Patent:  6,926,908

Issued:  August 9, 2005

Inventors:  Robinson; Stuart (Nether Broughton, GB); Smith; Susan Stewart (Loughborough, GB)

Assignee:  Quadrant Drug Delivery Limited (Nottingham, GB)

Appl. No.:  218448

Filed:  August 12, 2002

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.

SUMMARY OF THE INVENTION

The present invention is based on the surprising discovery that it is possible to spray-dry a therapeutic agent at higher (and therefore commercially useful) concentrations than have been used previously, without the concomitant production of an undesirable high concentration of salt or other excipients. Such formulations show no substantial loss of activity after the drying process and have extended stability, by comparison with pre-spray-dried preparations. This discovery is of value for au therapeutic agents, in particular proteins and peptides to be administered via the lung.

According to the present invention, microparticles, obtainable by spray-drying a substantially pure solution of a therapeutic agent, consist essentially only of the agent. In a preferred embodiment, the microparticles consist essentially only of insulin and NaCl salt. Such microparticles may be held in a container at greater than 10% RH, and thus essentially at ambient humidity. The insulin microparticles are obtainable by dissolving Zn-insulin in acid, adding alkali to give an insulin solution, e.g. to a pH above 7, and spray-drying the insulin solution (which also contains a salt formed as a result of The dissolution process, or a buffer).

Preferably, the microparticles are non-crystalline amorphous

DESCRIPTION OF THE INVENTION

As indicated above, 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 feed stock solution to be spray-dried comprises primarily only therapeutic agent and solvent. Again, as described above, there may be a 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 μm, can be obtained. The mass median particle size is preferably 1 to 10 μm, 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 tryspin 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

The following Examples illustrate the invention.

EXAMPLE 1

A solution of bovine or human insulin for spray-drying is typically prepared in the following way. 5 g insulin is dissolved in 70 ml 0.05 m HCl, after which the solution is back-titrated with sufficient IM NaOH to reform a solution from the isoelectric point precipitate. According to the final concentration required, water is added to make to volume. Approximately 4.8 ml 1M NaOH is required, in this Example. The solution is then spray-dried using a Mini spray drier with an outlet temperature of approximately 87° C. and a solution feed rate of approximately 0.75 g/min

Reverse Phase High Performance Liquid Chromatography (RP-HPLC) was used to assess the stability of insulin, under the following conditions.
 

Under these conditions, bovine insulin has a retention time of approximately 7.4 minutes.

A peak attributable to deamidated insulin is located at the failing edge of the main peak. The extent of deamidation is used to indicate stability and is calculated by expressing The area of the deamidation peak as a percentage of the total peak area. Total degradation is expressed as the area of all degrading peaks as a percentage of the total peak area.
 

The results indicate that the extent of both deamidation and total degradation is increased with time, for all the batches evaluated. Additionally, the data suggest that spray drying appears to confer additional stability to the protein, in that the bovine crystalline insulin control suffers increased degradation in comparison to the microparticle formulations at comparable timepoints after storage at 30° C./60% RH.

To investigate whether this was also seen with human insulin, human insulin microparticles were prepared (by the same general procedure as that described above) and placed on accelerated stability at 40° C./75% RH. All samples were analysed by RP-HPLC at the initial time point, and also after 1 week, 2 weeks and 5 weeks.

Comparing Tables 3 and 4, the microparticle formulation of human insulin is less prone to degradation, showing only 3.32% total degradation for the 5 weeks at 40° C./75% RH compared to 8.40% total degradation for the material stored as received under the same conditions.

Pikal and Rigsbee (1997), supra, although working on a lyophilised form of insulin, might be understood to substantiate the findings reported herein.
 

Claim 1 of 53 Claims

1. Microparticles, obtainable by spray-drying a substantially pure solution of a therapeutic agent, wherein the microparticles consist essentially only of the therapeutic agent having its therapeutic activity when administered to the lung, and further wherein the therapeutic agent is a protein or peptide.

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