JP2003206227A - Medicinal composition for nasal administration - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a composition for nasal administration, improving the efficiency of in vivo absorption of a medicine. <P>SOLUTION: This composition for nasal administration contains a crystalline cellulose and/or partially pregelatinized starch particles, having specific particle diameters as a carrier of the medicine. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition which is characterized in that its dosage form is granular and passes through the nasal mucosa. More specifically, the present invention relates to a granular composition for intranasal administration of physiologically active peptides including insulin.

[0002]

2. Description of the Related Art At present, insulin as a therapeutic drug for diabetes is clinically used as an injectable preparation, and a relatively simple subcutaneous injection preparation is mainly used for self-injection. However, due to its nature as an injectable preparation, patients have to self-inject one to four times a day before meals, which is one of the problems of diabetes treatment.
It has become one. Similarly, many peptide drugs other than insulin are administered as injectables, and simple administration forms are being developed.

In particular, preparations for intranasal administration have been proposed in order to eliminate the complexity of the administration method. For example, Japanese Patent Publication No. 62-42888 discloses such a dosage form.
An insulin preparation is described in which crystalline cellulose is used as a base material and the 90% by weight particle size is in the range of 20 to 150 μm. In this formulation, insulin is used in the examples described in the publication under the suggestion that "the physiologically active polypeptides are preferably water-soluble in consideration of absorption from the nasal mucosa." Soluble insulin powder obtained by dissolving with 0.1N HCl aqueous solution and freeze-drying was mixed with crystalline cellulose and sieved.
A composition is obtained in which 0% by weight or more of the particles are 75 to 149 μm.

JP-A-10-59841 (EP-A
1-94326)).
As compared with the composition described in JP-A-42288, even a highly water-soluble drug, a highly lipophilic drug, and a peptidic drug having a large molecular weight are excellent in absorbability from the nasal cavity and the maximum blood concentration is increased. Compositions that have been demonstrated to do are described. According to this publication, the above-mentioned effects are the same as those suggested by JP-B-62-42888 in that a water-absorbing and gel-forming base material (eg, hydroxypropyl cellulose, etc.) is used. It is claimed to be achievable by positively using it in combination with a crystalline cellulose aggregate containing particles larger than 150 μm.

However, beginning with these prior art,
The present inventors do not know that there is information that a formulation for nasal administration of insulin has been put to practical use.

[0006]

According to the above-mentioned prior art, a certain result has been obtained with respect to the improvement of the in vivo absorbability of the drug and the improvement of the blood concentration thereof. However, there is still a strong demand for providing a composition which exhibits higher drug bioabsorption and / or drug efficacy efficiently.

[0007]

DISCLOSURE OF THE INVENTION The inventors of the present invention have disclosed the above Japanese Patent Publication No. 62-42888 and Japanese Patent Laid-Open No. 10-598.
Contrary to what is suggested in Japanese Patent No. 41, the sieving particle size is 15
Using a crystalline cellulose powder having a specific particle size distribution of less than 0 μm, and in combination with such a powder,
Surprisingly, a composition for nasal administration prepared by using a partially pregelatinized starch powder having a certain particle size alone is surprising,
It has been found that the absorption and efficacy of the drug can be significantly increased compared to prior art compositions.

The present invention is based on such knowledge.

Therefore, according to the present invention, there is provided a granular nasal composition comprising a drug powder and a substantially water-insoluble polysaccharide powder as a carrier for the drug, wherein the drug has a molecular weight of 30, 000 or less of physiologically active peptides, and the water-insoluble polysaccharide has a crystalline cellulose powder in which 85% by weight or more of particles are distributed over a part or the whole of the sieving particle size range of 20 to 60 μm and the average particle size is Two
A composition is provided which is at least one selected from partially pregelatinized starch powder having a size of 0 to 100 μm. In addition, among such compositions, a composition in which the drug is insulin and the water-insoluble polysaccharide is only the crystalline cellulose is disclosed in Japanese Patent Application No. 2001-2 of the present applicant.
It is also an invention in the specification of 04784.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The drug of the present invention has a molecular weight of 30,00, which has the object of the present invention, that is, high intracorporeal absorbability can be obtained by intranasal administration, and which can exert its efficacy efficiently.
There can be mentioned 0 or less physiologically active peptides.

Examples of the physiologically active peptide having a molecular weight of 30,000 or less include insulin, growth hormone, calcitonin, glucagon, glucagon-like peptide-1 (G
LP-1), interferon, interleukin, erythropoietin, luteinizing hormone-releasing hormone, somatostatin, vasopressin, oxytocin, enkephalin, adrenocorticotropic hormone, growth hormone-releasing hormone, granulocyte colony-stimulating factor, parathyroid hormone,
Thyrotropin-releasing hormone, angiotensin,
Examples include prolactin and luteinizing hormone. These drugs are not limited by their origin, preparation method, etc., and may be modified or modified to some extent as long as they have desired effects. Taking insulin as an example, clinically used human insulin, bovine purified insulin, porcine purified insulin, semi-synthetic human insulin, human isoinsulin, etc., as well as human insulin obtained by utilizing gene manipulation technology And all variants thereof having the same activity as human insulin are included in the above-mentioned insulin.
In the present invention, these insulins are preferably used in the form of powder, and even if a modified form of insulin is used, the insulin powder is extremely insoluble or almost insoluble in water (corresponding insulin Powder 1
The amount of solvent required to dissolve g is 1000 mL or more and 1
Less than 0000 mL, or 10,000 mL or more; 13th
The revised Japanese Pharmacopoeia, General Rules A-51) can be preferably used. Many of the above-mentioned insulins are extremely insoluble or hardly soluble in water as they are, and can be the insulin powder according to the present invention as they are.

[0012] The above-mentioned drug powder including insulin can be crystalline or amorphous fine powder,
A plurality of drug powders that are finer than the cellulose particles and partially pregelatinized starch particles that make up the crystalline cellulose powder described below and are generally on the surface of these particles or in the microstructure (eg, pores) of the surface. Adheres,
Or it can be of a size that can be encapsulated. Generally, various drugs that are commercially available in the form of bulk drug can be used as they are.

The "crystalline cellulose powder (or particles)" referred to in the present invention generally means that the α-cellulose obtained as a pulp from a fibrous plant is partially depolymerized with an acid to form a water-insoluble portion. A purified product can be given.
Crystalline cellulose powder obtained from rayon fibers and the like can also be used as long as the object of the present invention is met. More specifically, for example, JP-B-39-12469 and JP-B-56-381.
No. 28, Japanese Examined Patent Publication No. 61-21201 and Japanese Examined Patent Publication 5-3
From Avicel (trademark) (Avicel (trademark)) types as described in 8732 and their variants,
If necessary, use a high-speed rotary impact grinder or air-flow grinder to reduce the size and / or increase the bulk density and finely pulverize, and then classify or screen into an aggregate of particles of the desired size. The crystalline cellulose powder thus obtained can be used in the present invention.

Such crystalline cellulose powder is usually obtained by depolymerization as described above, but the average degree of polymerization thereof is not limited as long as it is in accordance with the object of the present invention. However, in the present invention, in general, 15
~ 400, preferably 20-250, more preferably 3
It can be selected from crystalline cellulose having an average degree of polymerization of 0 to 50. The crystalline cellulose powder is not limited, but those having a bulk density of 0.20 to 0.65 g / cm ³ can be used, but preferably 0.22 to 0.40 g / c.
can be m ³ . In addition, such bulk density is S
It is a value when measured using a cott volumeter.

An important factor required for the crystalline cellulose powder that can be used in the present invention is the size and distribution pattern of the crystalline cellulose particles constituting the powder. When these are expressed by the screened particle size range, it is necessary that about 85% by weight or more of particles are present in a part or the entire range of 20 to 60 μm.

In the present specification, when the particle size is hereinafter expressed, it means the "sieve particle size" unless otherwise specified.

On the other hand, the partially pregelatinized starch powder (or particle) which can be used as the other carrier according to the present invention is, from the standpoint of the present invention, any partially pregelatinized starch by any means. It may be. However, although not limited, corn starch physically, that is, heat-modified, is preferable. In addition, such a partially pregelatinized starch is substantially water-insoluble. The term “substantially water-insoluble” means that the content of the water-soluble component at room temperature is 5% or less, preferably 2.5% or less. In addition, "partial alpha" is in pure water,
The degree of swelling when measured at a temperature of about 20 ° C. is about 8 to
It is preferably adjusted to 9 cm ³ / g.

Such starch is used by classifying it into those having an average particle size of 20 to 100 μm, preferably about 32 μm or less. As a typical example, partially pregelatinized starch (swelling degree 8 to 9 cm ³ / g) available from Asahi Kasei under PCS (trademark) is used after being classified if necessary.

In the above powder, when the particle size distribution is expressed under the term "partially or entirely", for example, crystalline cellulose powder has a particle size range of 20 to 60 μm, or a partial area thereof. For example, 20 to about 40
μm, 20 to about 55 μm, about 25 to about 38 μm, about 25
To about 53 μm, or about 38 to about 53 μm, etc., means a crystalline cellulose powder in which about 85% by weight or more of particles are distributed. Therefore, as such a concrete example, Avicel (trademark) PH-F20 or PH-M15 can be classified or used as it is on the market. preferable,
The crystalline cellulose powder having a particle size distribution is not limited, but 10% by weight or less of particles having a particle size of less than 25 μm, 20 to 60% by weight of particles having a particle size of 25 to 38 μm, and more than 38 μm and up to 53 μm. 20 to 20
Examples thereof include those having a particle distribution such that particles having a particle size of more than 60% by weight and 53 μm are the rest (ratio of making total particles 100% by weight).

According to the present invention, the blending ratio of the insulin powder and the crystalline cellulose powder or the partially pregelatinized starch can be 1: 1 to 500, and more preferably 1: 2 to 100 on a weight basis.

The composition according to the present invention comprises the above-mentioned insulin powder and crystalline cellulose aggregate by means commonly used for homogeneously mixing a drug in powder form and a solid carrier (for example, a mixer or mixer). It can be prepared by homogeneous mixing. If necessary, a step of removing particles smaller than 10 μm or particles larger than 100 μm may be added thereafter, but according to the experience of the present inventors, such a removing operation is rarely necessary.

In addition to the above components, the composition according to the present invention may contain other carriers or substrates, excipients, preservatives, preservatives, absorption promoters, etc., as long as they do not adversely affect the purpose of the present invention. Can be included. For example, as another carrier,
Examples thereof include cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and methylcellulose as described in JP-A-10-59841. Further, as the absorption enhancer, as described in US Pat. No. 5,731,303, it is also possible to use angelica, which is an essential oil, and its components, such as cyclopentadecanolide. it can. When such other carrier or absorption enhancer is used, the resulting composition has a particle size of 70 μm to 100 μm, preferably 20 μm to 60 μm.
It is preferable to screen so that the m-those exceeds 80%.

[0023]

EXAMPLES The present invention will be further described below with reference to specific examples of the composition for intranasal absorption of physiologically active peptides according to the present invention, but the present invention is not intended to be limited to these. The composition for nasal absorption was intranasally administered to cynomolgus monkeys (body weight 3 to 7 kg) once. The administration method is
Each composition was filled in a capsule and administered intranasally using an intranasal administration device (jet riser, Unisia Jex Co., Ltd.). (1) Pharmacokinetics and pharmacological test of insulin in cynomolgus monkeys Water-insoluble insulin powder (Intergen, 28.7)
IU / mg) 35 mg (as-received insulin) and crystalline cellulose (Asacel Kasei: Avicel ™ P)
A composition for nasal absorption was prepared by thoroughly mixing H-101 and Avicel (trademark) PH-F20) with 965 mg each in a mortar. Further, 100 mg of poorly water-soluble insulin powder was dissolved in 1 mL of 0.1N hydrochloric acid, and then water-soluble insulin was prepared by freeze-drying an insulin solution containing 40 mL of purified water. The water-soluble insulin powder (27. 7 IU / m
g) A composition for nasal absorption prepared by thoroughly mixing 36 mg of the above-mentioned crystalline cellulose with 964 mg in a mortar was intranasally administered to cynomolgus monkeys (n = 6). Serum insulin concentration and serum glucose concentration after administration were measured.

The insulin and glucose concentrations were measured by the EIA method (enzyme immunoassay) and Glck, respectively.
-By the G-6-PDH method.

The pharmacokinetic parameters (mean ± standard deviation) determined from the serum insulin concentration are shown in Table 1 below.

FIGS. 1 and 2 show changes with time in serum insulin concentration and glucose concentration of the above nasal absorption composition, respectively. Table 2 shows the raw data for Figure 1.
~ 5.

[0027]

[Table 1]

[0028]

[Table 2]

[0029]

[Table 3]

[0030]

[Table 4]

[0031]

[Table 5]

From Table 1, when 16 IU of insulin per animal was intranasally administered, the poorly water-soluble insulin, Avicel (trademark) PH-F20, was the most excellent in absorbability of insulin, followed by the water-soluble insulin Avicel (trademark). ) PH-F20, Avicel of poorly water-soluble insulin
(Trademark) PH-101, Avic of water-soluble insulin
EL (TM) PH-101. That is, the poorly water-soluble insulin Avicel (trademark) PH-F20 and Avi
It was found that cel ™ PH-101 and the water-soluble insulin Avicel ™ PH-F20 composition achieve higher insulin absorption compared to the water-soluble insulin Avicel PH-101 composition. It was (2) Pharmacokinetic study of human growth hormone in cynomolgus monkey Human growth hormone powder (human growth hormone 14.3%
Containing 17.5 mg of Wako Pure Chemical Industries, Ltd. and crystalline cellulose (manufactured by Asahi Kasei: Avicel (trademark) PH-F2).
0) A composition for nasal administration prepared by thoroughly mixing 62.5 mg in a mortar, on the other hand, as a control, crystalline cellulose (Avicel (trademark) PH-1 manufactured by Asahi Kasei)
The composition for intranasal administration prepared in the same manner as described above using 01) as a carrier was intranasally administered to cynomolgus monkeys (n = 3) once, and the serum human growth hormone concentration was measured.

The human growth hormone concentration was measured by the EIA method (enzyme immunoassay).

Human growth hormone concentration (difference from the initial value)
The pharmacokinetic parameters (mean ± standard deviation) determined from Table 6 are shown in Table 6 below.

FIG. 3 shows the time course of human growth hormone concentration (difference from the initial value). Raw data relating to FIG. 3 are shown in Tables 7 and 8 (each pharmacokinetic parameter is
It has the same meaning as in Table 1. ).

[0036]

[Table 6]

[0037]

[Table 7]

[0038]

[Table 8]

From Table 6, Avicel ™ PH-F
It was found that the composition for nasal administration of human growth hormone having 20 as a carrier exhibited a clearly higher absorbability as compared with the case of Avicel (trademark) PH-101 (see also FIG. 3). (3) Pharmacological test of insulin in cynomolgus monkey when pregelatinized starch is used as a carrier or an additive Water-insoluble insulin powder (Intergen, 28.7)
IU / mg) and (1) Avicel ™ P
A composition using H-F20 as a carrier (hereinafter, F20) was compared with the following composition.

Partially pregelatinized starch (made by Asahi Kasei:
PCS (trademark) classified to 32 μm or less,
35 mg of poorly water-soluble insulin powder (Ingen, 28.7 IU / mg) using s-PCS) as a carrier
(Insulin as obtained) and s-PCS 965m
Insulin composition obtained by thoroughly mixing g with g in a mortar (hereinafter, in-PCS), the in-PCS and Av
Icel (trademark) PH-F20 as a carrier, poorly water-soluble insulin powder (Intergen, 28.7 IU / m)
g) 35 mg (insulin as obtained) and crystalline cellulose (Avicel (trademark) PH-F2 manufactured by Asahi Kasei Corp.)
0) A composition obtained by mixing 1: 1 of an insulin composition (hereinafter, F20) obtained by thoroughly mixing 965 mg with mortar (hereinafter, in-PCS + F20 (1: 1)),
A composition obtained by adding 1% and 10% s-PCS to F20 (hereinafter, F20 + 1% s-PCS, F20 + 10% s
-PCS) was used to intranasally administer 16 IU of insulin to each cynomolgus monkey (n = 3 to 6). Serum insulin concentration and serum glucose concentration after administration were measured.

The insulin and glucose concentrations were measured by EIA method (enzyme immunoassay) and Glck method, respectively.
-By the G-6-PDH method.

Table 9 below shows the pharmacokinetic parameters (mean ± standard deviation) determined from the serum insulin concentration and the pharmacological parameters determined from the serum glucose concentration.

FIG. 4 and FIG. 5 show changes with time of the reduction rates (%) of serum insulin concentration and glucose concentration of the above nasal absorption composition, respectively. Further, raw data relating to FIG. 5 are shown in Tables 10-14.

[0044]

[Table 9]

[0045]

[Table 10]

[0046]

[Table 11]

[0047]

[Table 12]

[0048]

[Table 13]

[0049]

[Table 14]

From Table 9, AAC _0.4 / AUC _0.4 is F20.
0.5 of in-PCS, in-PCS + F20
(1: 1), 0.9 for F20 + 10% s-PCS
Significantly higher than 1.6, suggesting that the use of PCS as a carrier or an additive is effective in lowering blood glucose, though the absorption of insulin is inferior to the composition using F20 as a carrier. (See also Figures 4 and 5).

[Brief description of drawings]

FIG. 1 is a graph showing changes in serum insulin concentration after intranasal administration of each composition in cynomolgus monkeys.

FIG. 2 is a graph showing changes in serum glucose concentration after intranasal administration of each composition in cynomolgus monkeys.

FIG. 3 is a graph showing changes in serum human growth hormone concentration (difference from the initial value) after intranasal administration of the composition in cynomolgus monkeys.

FIG. 4 is a graph showing changes in serum insulin concentration after intranasal administration of each composition in cynomolgus monkeys.

FIG. 5 is a graph showing changes in the rate of decrease (%) in serum glucose concentration after intranasal administration of each composition in cynomolgus monkeys.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Toshishi Harita             815-5 Yoshino-cho, Kagoshima City, Kagoshima Prefecture F term (reference) 4C076 AA29 AA31 BB25 CC30 EE30A                       EE31A EE38A FF02 FF68                 4C084 AA03 BA44 DA12 DA21 DB07                       DB09 DB11 DB14 DB21 DB22                       DB23 DB24 DB25 DB28 DB29                       DB31 DB32 DB34 DB35 DB56                       MA01 MA05 MA41 MA59 NA10                       NA11 ZC03

Claims (6)

[Claims] 1. A granular composition for nasal administration comprising a drug powder and a substantially water-insoluble polysaccharide powder as a carrier for the drug, wherein the drug has a molecular weight of 30,000 or less. Crystalline cellulose powder in which 85% by weight or more of the water-insoluble polysaccharide is distributed over a part or the whole of the sieving particle size range of 20 to 60 μm, and a part having an average particle size of 20 to 100 μm. A composition which is at least one selected from alfa starch powder, provided that the water-insoluble polysaccharide contains at least the partially pregelatinized starch when the drug is insulin. 2. The composition according to claim 1, wherein the partially pregelatinized starch has an average particle size of 32 μm or less. 3. The composition according to claim 2, wherein the partially pregelatinized starch powder is obtained by physically modifying corn starch and has a swelling degree of 8 to 9 cm ³ / g. 4. When the crystalline cellulose powder is expressed by sieving particle size, particles of less than 25 μm are 10% by weight or less, particles of 25 to 38 μm are 20 to 60% by weight, and particles of more than 38 μm to 53 μm are 20% by weight. ~ 60% by weight
The composition according to any one of claims 1 to 3, wherein particles having a particle size of more than 53 µm have a residual particle distribution (a ratio of total particles to 100% by weight). 5. The crystalline cellulose powder is 0.20 to 0.6.
The composition according to claim 1, which has a bulk density of 5 g / cm ³ . 6. The drug is insulin, growth hormone, calcitonin, glucagon, glucagon-like peptide-1, interferon, interleukin, erythroboetin, luteinizing hormone-releasing hormone, somatostatin,
Claims 1 to 1 selected from the group consisting of vasopressin, oxytocin, enkephalin, adrenocorticotropic hormone, growth hormone releasing hormone, granulocyte colony stimulating factor, parathyroid hormone, thyroid stimulating hormone releasing hormone, angiotensin, prolactin and luteinizing hormone. 5. The composition according to any one of 5 above.