JP2000229859A - Stable pernasal preparation of buprenorphine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a pernasal preparation of buprenorphine capable of rapidly removing pain of patients and simply administering and being physically stable. SOLUTION: This powdery pernasal preparation comprises buprenorphine, a slightly water-soluble and water-absorbable base, a water-soluble and gel- forming base and stearic acid. It is preferable that the slightly water-soluble and water-absorbable base is one or two compounds selected from a group comprising crystalline cellulose, α-cellulose, crosslinked dextrin, chitin and chitosan and the water-absorbable and gel-forming base is a lower alkyl ether of cellulose.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a stable nasal powder of buprenorphine. More specifically, the present invention relates to a powdery nasal preparation comprising buprenorphine, a poorly water-soluble and water-absorbable base, a water-absorbable and gel-forming base, and stearic acid. The present invention is easily administered to a patient having pain due to cancer disease or surgery by a doctor, a nurse, the patient, and the like, and in order to eliminate the pain promptly, absorption from the nasal cavity is rapid and The purpose of the present invention is to provide a nasal powder of buprenorphine which is highly efficient and stable in the preparation.

[0002]

2. Description of the Related Art Cancer pain, postoperative pain and the like are extremely painful and intolerable pains for patients. For these pains, drugs or non-narcotic opioids are mainly used as therapeutic drugs, and as a dosage form of these drugs, for example, morphine, which is a drug, is marketed as an injection, suppository, orally,
Fentanyl citrate, a drug, is marketed as an injection and a tape, and buprenorphine, a non-narcotic opioid, is marketed as an injection and a suppository, each of which has an effect on pain relief.

[0003] Also, Journal of Pharmaceutics and Pha
In ramcology Vol. 41 803-805 1989, a nasal solution of buprenorphine is shown as a convenient dosage form. Drug absorption through the nose is faster than suppositories, oral preparations, etc., can be expected to be as effective as injection administration, and its administration method is relatively simple for both users and non-users It has been known.

[0004] As described above, suppositories and injections are already on the market for preparations containing buprenorphine as the main drug. Also,
Currently, other dosage forms such as tapes and oral preparations are under development in Japan and overseas. However, if you are in the position of a distressed patient or caregiver,
They do not completely satisfy the needs of patients and caregivers. In other words, patients are eager to escape pain quickly, and caregivers want to respond easily and quickly to their wishes. The blood concentration before the effect takes effect has some time to be achieved, during which the patient has to fight the pain. Also, suppositories are not hygienic due to their administration route, and are difficult to use for patients and caregivers. In addition, injections
The drug can reach the blood promptly and provide quick pain relief, but is ultimately invasive, can only be administered to qualified personnel such as doctors and nurses, and therefore requires hospital visits There are also problems such as that.

[0005] Therefore, as a means for expressing the simplicity of administration and the rapid pain-relieving effect, drug administration through the nose can be considered as described above. The above-mentioned Journal of Pharmaceu
ticsand Pharamcology Vol. 41 803-805 1989 shows that administration of a nasal solution of buprenorphine to a healthy person quickly showed an effective blood concentration of the drug. However, even with this formulation, the physical stability of the active ingredient buprenorphine in the formulation is very problematic,
It is important to overcome this stability problem in order for the formulation to be able to withstand clinical use in patients.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to rapidly relieve a patient's pain and to administer it easily,
Another object of the present invention is to provide a nasal powder preparation of buprenorphine which is physically stable.

[0007]

That is, the present invention provides a powdery nasal preparation comprising buprenorphine, a water-insoluble and water-absorbing base, a water-absorbing and gel-forming base, and stearic acid. Is provided.

[0008]

DETAILED DESCRIPTION OF THE INVENTION The present invention is a powdery nasal preparation comprising buprenorphine, a poorly water-soluble and water-absorbable base, a water-absorbable and gel-forming base, and stearic acid.

[0009] Buprenorphine of the present invention is a partial agonist of morphine, and its analgesic action is known to be several tens of times that of morphine. In other words, buprenorphine exerts a pain-relieving effect by suppressing the central nervous system pain conduction system. It is known to be effective. Currently, buprenorphine hydrochloride, injection,
Suppositories are on the market. Buprenorphine of the present invention,
It also includes buprenorphine, which is present as a salt with a pharmaceutically acceptable acid, preferably buprenorphine hydrochloride, which is the hydrochloride salt.

The poorly water-soluble and water-absorbing base material of the present invention (hereinafter sometimes abbreviated as “slightly water-soluble base”) is selected from the group consisting of crystalline cellulose, α-cellulose, crosslinked dextran, chitin, and chitosan. One or more.

Among these, the poorly water-soluble base of the present invention is preferably one or more selected from the group consisting of crystalline cellulose, α-cellulose and chitosan, and especially preferred is crystalline cellulose. Can be given as

The water-absorbing and gel-forming base of the present invention (hereinafter sometimes abbreviated as "gel-forming base") is preferably a lower alkyl of cellulose, particularly hydroxypropylcellulose, hydroxypropylcellulose. It is preferable that the base is one or more bases selected from the group consisting of propylmethylcellulose, methylcellulose, hydroxyethylcellulose and sodium carboxymethylcellulose. Among them, particularly preferred is hydroxypropylcellulose.

[0013] Hydroxypropylcellulose preferably has a 2% aqueous solution having a viscosity of 150 to 4,000 cps. The viscosity referred to herein is a kinematic viscosity and is measured by a viscometer such as Cannon-Fenske, for Cannon-Fenske opaque liquid, Ubbelohde, Ostwald or the like. Above all, measurement with an Ubbelohde viscometer is preferred because of its high accuracy. The viscosity values described herein are 37 ° C.
Under the environment described above, using an Ubbelohde viscometer manufactured by Shibata Scientific Mechanical Engineering Co., Ltd. Some hydroxypropyl celluloses have lower viscosities, but 150 c
When a substance having a viscosity lower than ps is used, the effect of increasing the maximum blood concentration of the present invention may not always be sufficient.

Preferred combinations of the gel-forming base and the poorly water-soluble base of the present invention include combinations of the above-mentioned preferred examples. Particularly preferred combinations are hydroxy as the gel-forming base. Propyl cellulose and crystalline cellulose as a poorly water-soluble base can be mentioned.

The mixing ratio of the gel-forming base and the poorly water-soluble base used in the present invention is 1:99 to 35:65 by weight.
It is preferable that the amount of the gel-forming base is small, because higher and faster nasal absorption of the drug can be achieved.
The ratio is preferably 0 to 20:80.

[0016] The stearic acid of the present invention is originally known for use as a lubricant in pharmaceutical preparations, and the use concentration in this case is 0.3 to 1%, which is common knowledge to those skilled in the art. . As a result of intensive studies, the present inventors have found that stearic acid also functions as a lubricant as is known, but stabilizes the preparation by adding it in an amount larger than its general use amount. This shows that there is a correlation between the amount of stearic acid added and the stability (see Examples), and that the stabilizing effect of the present invention was not observed with other lubricants such as magnesium stearate and talc (control See example). Therefore, regarding the content of stearic acid of the present invention, 0.1.
It is preferably 1 to 10%, and since there is a correlation between the amount of stearic acid added and the stability as described above, 1 to 5%, which is more than 0.5% used as a lubricant, is preferred. It is particularly preferable because it leads to further stabilization.

In the nasal preparation of the present invention, it is preferable that the particle size of the drug is 150 μm or less because the drug is efficiently deposited in the nasal cavity after administration.
It is preferable that the average particle size be 1 to 100 μm, more preferably 1 to 20 μm, by spray drying or the like, since higher and faster nasal absorption of the drug can be achieved.

Further, in the nasal preparation of the present invention, the state where the drug is unevenly dispersed in the poorly water-soluble base rather than the gel-forming base can achieve higher and faster nasal absorption of the drug. Is preferred. The following techniques can be used as a pharmaceutical technique for achieving this uneven distribution. 1. The poorly water-soluble base and the drug are strongly mixed mechanically.
The gel-forming base is then mechanically weakly mixed with the mixture. 2. A drug is attached to the poorly water-soluble base by freeze-drying or spray-drying to obtain a base to which the drug is attached. Next, the obtained base material is pulverized and sieved so that the average particle diameter of 90% by weight or more of the particles is 10 to 250 μm to obtain a powdery substance. Thereafter, the gel-forming base is mechanically mixed with the powder. 3. The powder obtained by dissolving and dispersing the poorly water-soluble base and the drug in an organic solvent such as ethanol, and evaporating the organic solvent to dryness is adjusted to an average particle diameter of 10 to 250 μm. Then, the gel-forming base is mechanically mixed with the powder.

Among the above-mentioned production methods, in the case of the first production method and the second production method, the drug is dispersed more unevenly in the water-insoluble base than in the gel-forming base. This is preferred because it is easy. For example, when the drug and the poorly water-soluble base are mixed in the first production method, they can be mixed strongly, and then mixed weakly when mixed with the gel-forming base. When the gel-forming base of the second production method is mechanically mixed, it can be mixed strongly or weakly.

Here, the mechanical mixing in producing the composition of the present invention includes, for example, a V-type mixer which is a container-rotating type mixer, a cross rotary mixer, a double cone type mixer and the like, and a container. In addition to fixed mixers, such as universal mixers, ribbon mixers, automatic mortars, ball mills, and other mixers, such as high-speed mixers and power-full auto mixers, there is also manual mixing with a mortar.

The term "strong mixing" refers to manual mixing using a mortar, mixing using a fixed-type universal mixer, a ribbon mixer, an automatic mortar, a ball mill, or the like, or mixing using a high-speed mixer, a powerful automixer, or the like. In other words, this mixing mainly mixes the drug uniformly while adhering to the base. In addition, mixing weakly means mixing with a container-rotating V-type mixer, cross-rotary mixer, double-cone mixer, ball mill without using a ball, etc., and mainly the drug is uniformly dispersed independently of the base. Mixed.

Further, the nasal preparation of the present invention comprises the above-mentioned 1 to 3
Can be prepared by specifying the particle size of the base as described below, and these inventions are also preferable because they can achieve high and rapid nasal absorption of the drug. As a method for specifying the particle diameter of the base, for example, the average particle diameter of 90% by weight or more of the poorly water-soluble base is 10 μm to 250 μm.
The average particle diameter of particles having a gel forming base of 90% by weight or more is in the range of 10 μm to 105 μm, and the average particle diameter of the poorly water-soluble base is determined by the average particle diameter of the gel forming base. The method of preparing by making it larger can be mentioned.

Further, the average particle diameter of particles having a weight percentage of 90% or more of the poorly water-soluble base is 10 to 250 μm, and the average particle diameter of particles having a weight percentage of 90% or more of the gel-forming base is 10 to 6 μm.
A thickness of 5 μm is preferable because a further increase in the maximum blood concentration can be obtained.

Here, for example, the fact that the average particle size of the particles of 90% by weight or more of the base material is in the range of 10 to 250 μm means that the powder is classified manually or mechanically using a test sieve to classify the powder. This means that the openings passed through a 250 μm sieve but did not pass through a 10 μm sieve. At this time, while applying vibration, the weight of the powder on each sieve is weighed, and the fluctuation of the weight is 0.1%.
The time when the following conditions are reached is the end point of the vibration, and the time when the classification of the powder is completed.

Further, the expression that the average particle diameter of the poorly water-soluble base is larger than the average particle diameter of the gel-forming base means that even when the average particle diameters of both bases are within the above numerical ranges, respectively. It means that the numerical value of the average particle diameter of the base is larger than the numerical value of the average particle diameter of the gel-forming base.

As described above, when the powdery nasal administration composition of the present invention prepared by increasing the average particle size of the poorly water-soluble base to be larger than the average particle size of the gel-forming base, For a person skilled in the art, such as a method of mechanically mixing a poorly water-soluble base and a gel-forming base, the preparation can be prepared by a common method for producing a powdery preparation.

Further, it is preferable to prepare by the above-mentioned production methods 1 to 3 since a higher effect can be obtained.

The poorly water-soluble base and the gel-forming base of the present invention include the above-mentioned specific properties and a specific type of base, for example, starch and crystals, as long as the object of the present invention is not adversely affected. Known microspheres can be used as a base that can be used in a powdery composition for nasal administration such as cellulose, and in that case, those having a particle size of 10 to 150 μm are used. Is preferred.

The composition of the present invention may contain, if necessary, known binders, diluents, coloring agents, preservatives, preservatives, preservatives, and the like, in order to improve the physical properties, appearance, and odor of the preparation. And a flavoring agent may be added. Examples of the binder include starch, dextrin and the like; examples of the diluent include starch and lactose; examples of the colorant include red No. 2 and the like; examples of the preservatives include ascorbic acid and the like; For example, paraoxybenzoic acid esters and the like; as a flavoring agent, for example, menthol and the like can be mentioned.

The composition of the present invention is in a form suitable for administration as a pharmaceutical preparation. Such forms include capsules filled with the present invention in dosage units, which are sprayed intranasally with a suitable dosage device. In addition, the dosage unit amount of the composition of the present invention or a plurality of dosage unit amounts of the composition of the present invention is housed in an appropriate container, and the dosage unit amount of the composition of the present invention is administered in a single dose during the administration operation. Alternatively, they may be administered in divided doses.

[0031]

According to the present invention, buprenorphine, which was conventionally available only as an injection or suppository and could only be administered by physician injection or rectum by a third party, can be used when a patient feels pain. The patient himself can easily administer the drug, and can quickly remove pain, and the effect of the present invention on the medical site can be said to be great.

[0032]

EXAMPLES The present invention will be described below with reference to examples.

Examples 1 to 5 Nasal preparations containing buprenorphine as the main drug were prepared according to the formulations shown in Table 1 below.

[0034]

[Table 1]

Control Examples 1 to 3 Nasal preparations containing buprenorphine as the main drug were prepared according to the formulations shown in Table 2 below.

[0036]

[Table 2]

The nasal preparations of buprenorphine prepared according to Examples 1 to 5 and the nasal preparations of buprenorphine prepared according to Control Examples 1 to 3 were each placed in a glass vial in an amount of 20 mg and stored at 60 ° C. and 40 ° C. at 75% RH. The results of measuring the contents are shown in Table 3.

[0038]

[Table 3]

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor, Norie Suzuki 4-2-2 Asahigaoka, Hino-shi, Tokyo Teijin Incorporated Tokyo Research Center (72) Inventor Yasuhide Ueshima 4-2-2 Asahigaoka, Hino-shi, Tokyo Teijin Co., Ltd. Tokyo Research Center F term (reference) 4C076 AA29 BB25 CC01 DD41 EE32 EE37 FF63 FF68 4C086 AA01 CB23 MA03 MA05 MA43 MA59 NA03 NA10 ZA08 ZC41

Claims (8)

[Claims] 1. A powdery nasal preparation comprising buprenorphine, a poorly water-soluble and water-absorbable base, a water-absorbable and gel-forming base, and stearic acid. 2. The method according to claim 1, wherein the water-insoluble and water-absorptive base is one or more selected from the group consisting of crystalline cellulose, α-cellulose, cross-linked dextran, chitin, and chitosan. Nasal powder formulation. 3. The water-absorbing and gel-forming base comprises:
The powdery nasal preparation according to claim 1 or 2, which is a lower alkyl ether of cellulose. 4. The method according to claim 1, wherein the lower alkyl ether of the cellulose is one or more selected from the group consisting of hydroxypropylcellulose, hydroxypropylethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and calcium carboxymethylcellulose. A powdery nasal preparation according to any one of the preceding claims. 5. The method according to claim 1, wherein the content of stearic acid is 0.1% in the preparation.
The powdery nasal preparation according to any one of claims 1 to 4, which is 10 to 10% by weight. 6. The method according to claim 1, wherein the content of stearic acid is 1 to 1 in the preparation.
The powdery nasal preparation according to any one of claims 1 to 4, which is 0% by weight. 7. The powdery nasal preparation according to claim 1, wherein the content of the buprenorphine is 0.5 to 30% by weight in the preparation. 8. The mixing ratio of the hardly water-soluble and water-absorbing base to the water-absorbing and gel-forming base is 9 by weight.
The powdery nasal preparation according to any one of claims 1 to 7, which is in a range of 9: 1 to 70:30.