Link:  Pharm/Biotech Resources

Title:  Pernasally absorbable insulin preparations

United States Patent:  6,911,213

Issued:  June 28, 2005

Inventors:  Ryoichi; Nagata (Kagoshima, JP)

Assignee:  Translational Research Ltd. (Kagoshima, JP)

Appl. No.:  019396

Filed:  April 26, 2001

PCT Filed:  April 26, 2001

PCT NO:  PCT/JP01/03642

371 Date:  December 28, 2001

102(e) Date:  December 28, 2001

PCT PUB.NO.:  WO01/82950

PCT PUB. Date:  November 8, 2001

An insulin formulation with porous, spherical calcium carbonate composed of trabeculate or needle-shaped crystals, or an aggregation of the parallel intergrowth of these forms, as its carrier, will be presented. This formulation is beneficial for the treatment of diabetes.

DISCLOSURE OF THE INVENTION

To attain this aim, the present inventor investigated the effect of combinations of insulin and various carriers on the nasal absorption of insulin and, thereby the use of a specific calcium carbonate structure for intranasal insulin delivery was found to significantly increase blood insulin levels and significantly decrease blood-sugar levels.

The present invention was derived from the above-mentioned findings.

Accordingly, the present invention provides a formulation for the nasal absorption of insulin comprising a component composed of insulin and porous, spherical calcium carbonate as its carrier. In addition, the present invention provides a formulation for nasal absorption of insulin comprising a component composed of insulin and calcium carbonate as its carrier, in which said calcium carbonate comprises cubic or trigonal crystals (specifically originating from a pharmacopeial product), with a particle diameter in the range of 20-32 μm.

The present invention also provides, as another aspect, a method for the treatment of diabetes which comprises administering a component composed of insulin and porous, spherical calcium carbonate as its carrier into the nasal cavities of diabetics who need administration of an effective amount of insulin.

Additionally, the present invention provides, as another aspect, the use of a component composed of insulin and porous, spherical calcium carbonate as its carrier, to prepare a formulation for the nasal absorption of insulin.

BEST MODE FOR CARRYING OUT THE INVENTION

Any form of modified or unmodified insulin used in treating diabetes in humans may be used with the invention, regardless of its origin. Accordingly, any human insulin, swine-derived refined insulin, semi-synthetic human insulin, human isoinsulin, etc. or any other human insulin obtainable by gene manipulation technology that has an activity similar to that of human insulin can be used as "insulin" with the present invention.

The calcium carbonate to be used as a carrier is either porous and spherical in form or substantially composed of cubic or trigonal crystals with a particle diameter in the range of 20-32 μm.

The above-mentioned term "porous spherical", as may be seen in FIG. 1, which shows an example of porous spherical calcium carbonate, means an aggregation of trabeculate or needle-shaped crystalline, or a parallel intergrowth of these, and the substantial form is spherical. Parallel intergrowth means a state of growth in which two or more crystals grow in parallel along a certain crystalline axis. It can be assumed that these crystals, or a larger number, converge to form a spherical entity, and thus the constituent particles become porous.

The porous, spherical calcium carbonate has a particle diameter in the substantial range of 18-115 μm. "Substantial range" herein means the range in which the same nature or behavior as that of an ideal particle is observed or is shown by all particles (100%). For instance, when the word "substantial" is used in relation to the range of particle diameter, it means that at least 70%, or preferably at least 90%, of related particles show a particle diameter within a specific range. The desirable particle diameter of the porous, spherical calcium carbonate in question is within the substantial range of 20-32 μm, while preferably, 100% of related particles should be within this range. In addition to the particle diameter being within the above-mentioned range, it is particularly desirable that the median particle diameter be 22 μm or greater and less than 30 μm.

Moreover, although not a porous sphere as described above, calcium carbonate with a particle diameter in the above-mentioned desirable range, such as a cubic or trigonal calcium carbonate crystal obtained from a classified, pharmacopeial product, even though principally calcite in form, will act as a significantly superior insulin carrier in comparison with calcium carbonate crystals of an identical nature with a particle diameter of 40-45 μm or greater.

Porous, spherical calcium carbonate with a particle diameter within the desirable range can be synthesized by a recognized method and, depending on the required classification, may be used in the present invention. In the context of the present invention, light calcium carbonate means a synthetic product. Synthetic calcium carbonate is generally produced by the calcination of limestone followed by recarbonization by aeration. In the course of such manufacture, any necessary additive that can promote or control the reaction may be used, and the process may be further controlled by regulation of the reaction temperature and agitation in order to synthesize desired forms of calcium carbonate. It is understandable, therefore, that synthetic calcium carbonate produced by this process for use in the present invention may contain magnesium and alkaline metals etc., on condition that these satisfy pharmacopeial requirements.

Table 1 shows an example of the distribution of porous, spherical calcium carbonate particle size that can be used in connection with the present invention, including those of a certain particle diameter that are classifiable.

The calcium carbonate used in connection with the present invention is characterized by having a relative surface area of 1.5 m²/g or greater (BET method). This is significantly higher than that of standard light calcium carbonate available on the market, which is usually 0.1-0.3 m²/g.

This calcium carbonate, or a classified product obtained through an appropriate sieve, may be combined, as a carrier, with any quantity of insulin as long as the insulin can be adsorbed or carried as a monolayer or multilayer. As a general rule, however, insulin can be combined within the range of 0.1-50%, but preferably 1-10%, of the total weight of a combined component. Said component can be prepared by malaxation of insulin and calcium carbonate with an appropriate quantity of water using a suitable malaxation apparatus, and subsequent freeze-drying.

The component may be used intact as for a formulation for the nasal absorption of insulin, as described in the present invention. Alternatively, when or after preparing said formulation, any mucosal absorption enhancer, stabilizer, preservative, etc. is can be combined with the formulation of the present invention with no negative effects It is advisable to store such formulations intact or in capsules in an airtight package. The formulation of the present invention for the nasal absorption of insulin obtained through the processes described above, therefore, provides significantly enhanced pharmacokinetic characteristics (e.g. maximum blood concentration, area under blood concentration curve, bioavailability). Known devices for nasal medication, including nasal sprays, can be used for nasal administration.

Dose levels are not specified, because they will vary according to medical condition, age, body weight etc; however, it is preferable that they should be set by a medical specialist in reference to information such as the pharmacokinetic parameters of cynomolgus monkeys as stated below.

Formulations for the nasal absorption of the present invention obtained through the procedures described above have not shown any toxicity greater than that of subcutaneously injected Novolin (trademark), a recombinant human insulin manufactured by Novo Nordisk A/S.

Claim 1 of 8 Claims

1. A formulation for the nasal absorption of insulin, which comprises a component composed of insulin and porous, spherical calcium carbonate as its carrier, said calcium carbonate having a relative surface area of 1.5 m²/g or greater (BET method) and the porous, spherical calcium carbonate has a particle diameter substantially in the range of 20-32 μm, wherein the insulin is adsorbed or carried on said carrier as a monolayer or multilayer.

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