JPH04305529A - Pharmaceutical for pernasal administration - Google Patents

Abstract

PURPOSE:To obtain a heparin pharmaceutical for pernasal administration is characterized in that a low-molecular weight heparin(LMWH) useful as a medicine is contained as an active ingredient. CONSTITUTION:A heparin pharmaceutical for pernasal administration is obtained by cleaving unfractionated heparin (UFH) with nitrous acid, fractionating the UHF, purifying the resultant fraction, reducing terminal aldehyde groups with sodium boron hydride and using the produced sodium salt of LMWH (KABI 2165(R), average molecular weight; 4000-6000; about 150U/mg) according to a normal pharmaceutical technique.

Description

[Detailed description of the invention]

0001

[Industrial Application Field] The present invention relates to low molecular weight heparin, which is useful as a pharmaceutical.
The present invention relates to a low molecular weight heparin preparation for nasal administration, which is characterized by containing heparin (hereinafter referred to as LMWH) as an active ingredient.

0002

[Prior Art] Usually heparin (unfractiona
ted heparin (hereinafter referred to as UFH) has a molecular weight of approximately 3,000 and contains sulfonylated D-glucosamine, D-glucuronic acid, and L-iduronic acid.
0 to 100,000 mucopolysaccharides (muco
liver, heart,
It is known to be produced in the kidneys, small intestine, etc. This U
FH is known to exhibit a strong blood coagulation inhibitory effect, and is widely used as an anticoagulant in hemodialysis and the like.

[0003] Furthermore, the present inventors have previously discovered and reported that this UFH has the effect of enhancing prostaglandin I2 production and is expected to be a therapeutic agent for diseases such as hypertension, bronchial asthma, and gastric ulcers (particularly Ganpei 1-308800)
.

[0004] Since this UFH is hardly absorbed from the gastrointestinal tract, it has had to be administered by injection in order to expect sufficient medicinal efficacy.

[0005] However, since administration by injection is limited to specialists and is painful during administration, there has been a desire to develop a simpler and more easily applied formulation.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a low-molecular-weight heparin preparation for nasal administration, which is characterized by containing LMWH, which is useful as a pharmaceutical, as an active ingredient.

[0007]

[Means for Solving the Problems] As a result of extensive research into the nasal absorption of heparin, the present inventors have discovered that UFH can be cut, fractionated, purified, or further chemically modified to an appropriate molecular weight. It has been found that heparin can be absorbed through the nasal mucosa.

For example, UFH is cleaved with nitrous acid and fractionated,
Sodium salt of LMWH (Kabi
2165, average molecular weight 4,400-5,600, about 1
By administering 50 U/mg) into the nasal cavity using a publicizer (Fujisawa), it is absorbed through the nasal mucosa and reaches an effective blood concentration.

[0009] As the active ingredient contained in the drug of the present invention, LMWH that has been cut to an appropriate molecular weight, fractionated, and purified is used.
MWH is preferred.

[0010] Such LMWH may be obtained by simply cleaving, fractionating, and purifying UFH to an appropriate molecular weight according to a conventional method, but it may also be obtained by further chemically modifying a part of it, or by using pharmacologically acceptable products thereof. It is preferable that the salt be used as a salt. As an example of this, LMWH or its sodium salt (Kabi 2165, average molecular weight 4,400 to 5,600, about 150 u/mg).

[0011] The safety of LMWH has already been confirmed regarding its toxicity, and the fact that it has already been widely used in actual treatments such as artificial dialysis suggests that there are no safety issues when applying it to the human body. .

The nasal preparation of the present invention can be formed into solid, liquid or semi-solid preparations, all of which are manufactured according to methods known per se.

For example, solid preparations include LMWH (Kabi2
165) Grind the simple substance into a fine powder, add an appropriate mucosal absorption enhancer if necessary, and mix well. The particle size is approximately 2
It is preferably about 0 to 250 microns.

[0014] In the case of liquid or semi-solid, if necessary,
It can be produced by adding pharmaceutical excipients used for adjusting solubilizers, pH adjusters, preservatives, thickeners, liquid preparations, etc., and according to conventional pharmaceutical techniques.

[0015] The dosage depends on the sex, weight, and
It is determined as appropriate depending on age, disease type and symptoms, etc., but in general, 20 to 200 mg (15 mg) per day for adults.
It is administered in one to several doses within the range of 3,000 to 30,000 U (0 U/mg).

[0016]

EXAMPLES The contents of the present invention will be explained in more detail by the following experimental examples and examples. Note that each example does not limit the content of the present invention.

Example 1 150U/mg LMWH (Kabi2165) 5,0
After grinding 00,000U well into a fine powder, fill it into capsules, and each capsule contains 1,000U (100U).
5000 capsules with 0 U/ml) of active ingredient were obtained.

Experimental Example Kabi 21 was placed in the nasal cavity of a beagle dog (male, 12 kg).
65 After spraying 5,000U, 15, 30, 60
, 120, 240, 360 minutes later, vacuum blood collection tube (2 ml)
Citric acid blood was collected using The plasma of each collected blood was separated, and anti-Xa factor activity in the plasma was measured as an index of blood concentration using Test Team "Heparin" (Daiichi Kagaku). The results were as follows.

[Table 1]

Claims (2)

[Claims] 1. A nasal preparation characterized by containing low molecular weight heparin as an active ingredient. Claim 2: Average molecular weight of about 4,400 to 5,600
2. The preparation according to claim 1, which contains low molecular weight heparin as an active ingredient.