Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-02-26
2004-12-28
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S499000, C424S501000
Reexamination Certificate
active
06835389
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to powder compositions for nasal administration having an improved drug absorbability via nasal mucosa. More specifically, the present invention relates to powder compositions for nasal administration that exhibit high maximum blood concentration by using a drug having a specific particle size or a lyophilized drug, and a base material of a specific type or composition.
DESCRIPTION OF THE RELATED ART
Because, in non-peptide/protein drugs such as anti-inflammatory steroids, (1) local nasal mucosa can be a target as an active size, (2) an immediate action may be desired, and (3) some have low absorbability via oral administration, and the like, there has been a need for the development of drugs for nasal administration.
Many peptide/protein drugs are not readily absorbed into the body because, when orally administered, they tend to be decomposed by proteolytic enzymes in the gastrointestinal tract. Therefore, injection has to be used for therapeutic uses of these drugs in many cases. However, injections impose a heavy burden on patients because of pain, the need for hospital visits etc. Thus, there is a strong need, for these drugs, for the development of noninvasive administration regimen that can replace injections.
Nasal administration is a method of administration in which drugs are transported through the nasal mucosa into the blood circulation. Nasal administration is under intensive research as a non-injection type administration together with, for example, subcutaneous, ocular, rectal, and pulmonary administration and the like. Among the non-injection type administrations, nasal administration is easy to perform. In addition, since the blood system is more developed in the nasal mucosa compared to the skin, the ocular mucosa, the rectal mucosa, and the like, the nasal administration is thought to have excellent absorbability among the non-injection type administrations. Formulations for nasal administration have indeed been put into practice for some drugs. Furthermore, since, in nasal administration, drugs migrate into the blood more rapidly than in oral administration, immediate action almost equal to injections can be expected for nasal administration. However, the absorption of drugs thought nasal mucosa depends on the physical properties such as lipophilicity, molecular weight, and the like. It has been postulated that highly water-soluble drugs, highly lipophilic drugs, peptide/protein drugs having high molecular weight etc. generally have low absorbability. Thus, various methods are postulated to enhance absorbability of drugs through nasal mucosa.
For example, Japanese Examined Patent Publication (Kokoku) No. 60-34925 reports on a prolonged-action formulation for the nasal cavity comprising a cellulose ether and a drug.
Prolonged-action formulations for nasal cavity described in the above publication are formulations intended to adhere to the nasal mucosa and to gradually release the drug, and thereby it is possible to allow the drug to be absorbed via the nasal mucosa to effect prolonged release of the effective amount of the drug. However, since the prolonged-action formulation for nasal cavity described in said publication points to sustained release of the drug, enough ability has not been given, it is believed, to the function of promoting the absorption of the drug. Drugs exemplified in the preferred embodiment are anti-inflammatory steroids, analgesic anti-inflammatory drugs, anti-histaminics, and drugs having anti-allergic actions and the like, for which the maintenance of local drug concentration is more important than absorbability into the systemic blood circulation.
Thus, in the prolonged-action formulations described in the above publication, a high nasal absorbability could not be expected for highly water-soluble drugs, highly lipophilic drugs, and high molecular weight peptide/protein drugs. Thus, there is a strong need for the development of compositions for administration via the nasal mucosa that can be effectively utilized in terms of therapeutic effects and therapeutic efficiency.
Nolte et al. (Hormone Metabolic Research Vol. 22, 170-174, 1991) and Bruice et al. (Diabetic Medicine Vol. 8, 366-370, 1991) reported on insulin formulations for nasal administration that contained an absorption promoter for sodium glycolate or taurofusidic acid sodium. These absorption promoters, however, have a problem of irritating nasal mucosa, and have not been put into practical use.
On the other hand, Japanese Examined Patent Publication (Kokoku) No. 62-42888 reported on powder compositions for nasal administration having an excellent absorbability via the nasal mucosa, said compositions comprising polypeptides and a water-absorbing and water-slightly soluble base material. It is also reported that such compositions permit the nasal absorption of polypeptides without using such an absorption promoter.
However, even in the compositions of the above publication, the nasal absorption rate of polypeptides (the area under the blood concentration versus time curve (AUC) after nasal administration) does not exceed 10 to 20% of that after the injection administration. For example, according to Example 4 in the publication, the maximum blood concentration after administration of 10 units of insulin to rabbits in 200 &mgr;U/ml or less, or about 20% of that of the injection administration, and the absorption rate calculated from the AUC is estimated to be not greater than 10%.
The publication also describes a combined use of a water-absorbing and water-readily soluble base material and a water-absorbing and water-slightly soluble base material at a ratio of 0.1 to 60% by weight, most preferably 0.1 to 50% by weight relative to the water-absorbing and water-slightly soluble base material.
However, the publication only states that the objective or effect of such a combined use in sustained-release effects (sustained-release or prolonged action) compared to when a water-absorbing and water-slightly soluble base material is used alone.
Furthermore, the publication makes no mention of using non-peptide/protein drugs instead of polypeptides.
Furthermore, the publication illustrates, by way of example, many water-absorbing and water-slightly soluble base materials including crystalline cellulose and many water-absorbing and water-readily soluble base materials including hydroxypropyl cellulose. The publication, however, makes no mention that certain combinations of specific types, compositions, and particle sizes of these base materials can provide powder compositions for nasal administration that exhibit excellent maximum blood concentrations for peptide/protein drugs and non-peptide/protein drugs.
Furthermore, said publication states that it is important that 90% by weight or more of the particles of the composition have a particle size of 10 to 250 &mgr;m to attain good absorbability and that the drug (limited to polypeptides therein) and the base material can be present separately considering the state of the composition and the method of preparation. It is clear, in this case, that the particle size of the drug is not less than 10 &mgr;m. The publication does not make any mention either that particle size of less than 10 &mgr;m can lead to powder compositions for nasal administration having further excellent maximum blood concentrations.
The publication also suggests that lyophilized polypeptides may be used. However, it is a common knowledge among those skilled in the art that many of polypeptides should be lyophilized when they are present as solids because of their physical properties including stability. The publication makes no mention of using non-peptide/protein drugs that, in the lyophilized form, generally exhibit better stability compared to polypeptides, much less of using them to enhance maximum blood concentrations after the nasal administration thereof.
Japanese Unexamined Patent Publication (Kokai) No. 10-114645 describes powder formulations for nasal administration comprising powders of absorptive resin
Dohi Masahiko
Fujii Takao
Uejima Yasuhide
Azpuru Carlos A.
Sughrue & Mion, PLLC
Teijin Limited
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