JPS58189118A - Pernasal administration pharmaceutical - Google Patents

Abstract

PURPOSE:The titled pharmaceutical, containing a polypeptide having the physiological activity and a cyclodextrin, and having improved absorptivity of the polypeptide and high safety without a pain in administration. CONSTITUTION:A pernasal administration pharmaceutical containing a polypeptide having the phyiological activity, e.g. L-pyroglutamyl-L-histidyl-L-prolinamide (thyrotropin-releasing hormone) and a cyclodextrin (e.g. alpha-cyclodextrin). The polypeptide has a powerful hydrophilicity and low oil-water distribution coefficent and is not easily absorbed through the digestive tract due to the hydrolysis by enzymes in the wall of the digestive tract. The incorporation of the cyclodextrin increases the absorption of the polypeptide, and the pharmaceutical is highly safe in administration many times due to no taste, smell, toxicity nor irritation to the membranes.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a polypeptide preparation for nasal administration containing a physiologically active polypeptide and a cyclodextrin.

It has been known that pharmaceutical compounds that are highly hydrophilic and have a low oil-water partitioning ratio are not absorbed or are extremely difficult to absorb from the digestive tract. Physiologically active polypeptides are generally not only highly hydrophilic and have a low oil-water partitioning ratio, but also undergo hydrolysis by enzymes in the gastrointestinal tract or on the wall of the gastrointestinal tract.
Absorption from the gastrointestinal tract is extremely difficult. Therefore, in order to expect sufficient medicinal efficacy, the administration of these physiologically active polypeptides is limited to injections.
- Administration by injection is limited to specialists and is accompanied by pain in both the patient and the patient, so a simpler and easier to apply formulation is desired, especially during continuous administration.

On the other hand, cyclodextrin is a cyclic oligosaccharide that has one hydrophobic cavity in its molecule and serves as a monomolecular host molecule to form clathrate compounds with fat-soluble drugs, increasing the solubility of drugs, stabilizing them, and improving biological properties. It is an extremely safe compound that is well known to exhibit effects such as improving the availability of bioavailability and reducing bitterness [Pharmaceutical Journal No. 10]
Volume 1, page 857 (1981)]. However, cyclodextrin 1 is a physiologically active polypeptide! It does not form clathrate compounds with bathing drugs, and until now it has not been investigated as a mucosal absorption enhancer for these drugs.
Not at all.

In order to effectively exert the agglomeration effect of such physiologically active polypeptides that are poorly absorbed by digestion, the present inventors have conducted intensive research on formulations VC that improve bioavailability. It was discovered that the absorption of the polypeptide was significantly increased by using cyclodext-t-phosphorus, which has almost no interaction with the polypeptide, and based on this, the present invention was completed as a result of further research.

The present invention is a nasal preparation containing a physiologically active polypeptide and 7 clodextrin.

Examples of the physiologically active polypeptide used in the present invention include those that constitute two or more peptides.

Examples of the polypeptide include those having strong hydrophilicity and a low oil-water partitioning ratio. More specifically, examples include those having an octano-μm ice-water oil-water partition ratio of about 0.1 or less. The polypeptide preferably has a molecular weight of about 200 to 60,000.

Specific examples of the physiologically active polypeptide include L-biloglutami, vL-his6di1b-L-
Prolinamide (thyrotropin relieving hormone; hereinafter abbreviated as [TRHJ)] and these salts, especially tartaric salt (see Japanese Patent Application Laid-open No. 121273/1983), and formula (1) [Formula Inside, people are hydrogen, ayuki! , afμkiy, aμkoxyalkyl, hydrogyne~kiA
/1 run indicates Aμjob/. R is -CH2, ""CH2'CH2- or =
8- indicates -j-, R and other constituent amino acid residues O
Each may be in the L form, D form, or racemic form. ] or its right (see JP-A-52-116465). In this specification, among the compounds represented by the above formula (1), the compound represented by the following formula is referred to as [Dw-1417J.

Furthermore, the polypeptide includes luteinizing hormone (hereinafter abbreviated as [°LH-RHJ)].
, Mae is a homolog having the same effect as this, and is a homolog of the formula (1) (1 is Tyr or Phi, R3 is Gay or a D-type amino group, R4 is Leu, 11s or Hle, R5
is GIyNu R6 (R6 is ui or a lower alkyl group with or without a hydroxyl group) or NEI-R6 (R6
is the same meaning as above). [U.S. Pat. No. 3,853.8]
37, same No. 4,008,209. M No. 3,972゜8
59, British Patent No. 1,42F083. Proceedings of the Mat
io-nal Academy of 5cienc
eaOr the IJnitedStatss of
Marica ) % Volume 78 No. 6509-651
2 pages (1981) #Sho].

In the above formula (''), the D-type amino acid residue represented by R3 is, for example, a-D- having up to 9 carbon atoms.
'7minor l1l (e.g. D-Leu, Ile, Nle.

Val, NvaL, Mbu, Pha, Phg, Sar
, Thr, Met, Ala, 'I'rp, α-&ibu
etc., and they can be used as appropriate.
Of course, peptide (i) 0 acid derivatives and metal particles can also be used in the same way as peptide (1).

, 41 indicated by # with regard to amino acids, veg-6d, algae groups, etc. in the polypeptide represented by C(li),
[u P A C-I U B Collm1ss
ion on Biological Nomencla
Abbreviation by ture or common practice in the field J'@
They are based on abbreviations, and if an amino acid can have optical isomers, the L form is indicated unless otherwise specified.

1. In this specification, in the above formula (1), i
(1"kii -1, R2-Tyr, R3=D-L
eu, R4-Le! u.

R5-NHC)I2-(J3) [T
It is called A P-l 44 j.

In addition, further examples of the polypeptide include insulin, -7-tostatin, and growth hormone.

Glocktin, adrenocorticotropic hormone (MuCTH), metunona, thyroid stimulating hormone (Msl), thyroid stimulating hormone (TSH), luteinizing hormone (Ll (), Q follicle stimulating hormone (F'5I ()), vanpressin, vanpressin 84 bodies (See Desmoderesin [Journal of the Japanese Endocrine Society [Vol. 54, No. H45, pp. 676-691 (1978)] Tooxytocin, calcitonin, parathyroid hormone, gycagon, gastrin, secretin, pancreozymine, cholecynutokinin, angiotensin, human placenta Lactogen, human chorionic gonadotropin (FICG), enkephalin, enkephalin 84 C US patent @-+27
7394J+, European Patent Application Publication No. 31567], endoμ-in, interferon (I
xall, βM, rEW), urokinase, kallikrein, thymopoietin, su, isesin, hechityrin, deinofin, bombe/n, neurotensin, caerulein, plateikinin, substance P, chy3ctorphin, nerve growth factor, etc. .

Examples of the cyclodextrin used in the present invention include various cyclodextrin and cyclodextrin derivatives obtained by hydrolyzing fonan with #I or amylase.

As the cyclodextrin, for example, α (degree of 6
), β(] [degree of weight 7), and r (degree of weight 8) [Pharma V A Mo1.16. Mu 1 (1980)
, Pharmaceutical Journal Vol. 1.101. (10), 85787
3 (1981), Special Publication No. 53-31223 @Reference).

Examples of the cyclodextrin derivatives include tri-O-methyμ cyclodextrin [Chemical Pharmaceutical Pretin (Cha-mical & P
harg+acautical Bulletin)
Vol. 28, pp. 1552-1558, Sada (1980).
: InternationalIMltlon in
English), Volume 19, No. 344-362
Page (1980) β-Sho. ] etc.

The cyclodextrin used in the present invention includes α-
Cyclodextrins are particularly preferred.

The nasal preparation of the present invention can be manufactured according to methods known per se. For 7 hours, small amounts of pH adjusters, preservatives or thickeners (such as natural gums, cellulose derivatives, acrylic acid type polymers, vinyl polymers, etc.) or excipients are added.

The polypeptide-containing preparation Vi for nasal administration of the present invention is formed into a solid, liquid or semi-solid product. In the case of solid form, as in 1, the above components may be mixed to form a simple powder composition, but it may also be a freeze-dried product, with a particle size of approximately 20 to 250.
The one in micron size is good.

If it is liquid, a water-based solution, aqueous suspension, or oil-based suspension is best; if it is semi-solid, it is better to use an oil-based gel or ointment.

The proportion of each component in the preparation is approximately 0.005 to 501/V% of the polypeptide in the preparation when it is in solid form.

Preferably about 0. O1~30 W/Y%, cyclodextrin is about 2~99°995v/v%,
It is preferably about 5 to 99.991/7%. When in liquid or semi-solid form, the amount of poly'\glycdo in the formulation is about 0.01-50% V/V.

More preferably, the concentration of cyclodextrin is about 0.5 to 50 W/V%, and more preferably about 1 to 3 U W/V%. It is.

Solid preparations can be produced by methods known per se.

For example, cyclodextrin and, if necessary, excipients are added and mixed in a mixer, and then a surplus of the polypeptide dissolved in a small amount of water (KM) is added and kneaded. This is then dried at an appropriate temperature under vacuum, and the dried product is pulverized to form a solid preparation. Alternatively, if necessary, add water to the mixed bed of excipients to completely dissolve the polypeptide and cyclodachimetry 7, and then dehydrate and dry by freeze-drying or through-drying to obtain a dried product]
Tor (pulverize to obtain hardness).

Examples of the excipient include glucose, mannitol,
Inosol ~ -yv, i, sugar, lactose, fukuto > ,
-t, h-n, corn/starch, image Nh cellulose
Hydroxiderobi-ceylose, Hydro7'
+siglovir methylse A/lose, polyvinylpyrrolidone, etc.

Liquid formulation iIl! As a manufacturing method, it can be manufactured according to a method known per se. For example, an aqueous solution for nasal administration is prepared by mixing the Xelibede+2 and cyclodextrin with water,
It can be produced by dissolving, suspending, or emulsifying it in a MW solution or an aqueous solution. In addition, the oil-based suspension for nasal administration uses the melibedide and cyclodextrin as an oil-based base!
! It can be produced by clouding or emulsifying. The Il
Examples of liquid solutions include Seerenzen (36rensen).
) Detective@f (grgeb, Physiol,,1
2.393 (1912)], Clark-G
ark-Luba) ill impact (J, kct=
2, flL109.191 (1917)), Micll-vaina Yurusaki liquid (J, B
ioL Chew 49, 183(192+))+,
Michaelis buffer (DigW)
asaerstofTlonenkonzantrat
lon, p+186 (1914)], Kol.
thoff) buffer (Bio-cbsm, Z, 1
79, 410 (1926). Examples of the monooleic base include sesame oil, olive oil,
Toku Shichiro: 1 yen oil, soybean oil, cotton liao oil, peanut oil.

Flurin, Vaseline, Buffin. Isopar.

Silicone oil, fatty acids having 6 to 30 carbon atoms, or their glycerin or alcohol esters may also be used, and these may be used alone or in combination with 42al11 or more.

An oily gel or ointment can be produced from aqueous Ti according to methods known per se as methods for producing semi-solid preparations. For example, an aqueous 1fiy agent for nasal administration is prepared by preparing an aqueous solution or suspension of cyclodextrin;
If necessary, add a pH adjuster, preservative, etc. This #I solution is divided into two parts, an aqueous gel base is dissolved or dispersed in one half, and a stable gel is formed by heating or cooling appropriately.

An aqueous gel can be produced by dissolving the polypeptide in the other f# liquid and uniformly mixing the two.

One of the above adjustments can be made, for example, by adding acids, bases, spinal fluid, etc. during the manufacturing process of the preparation. The blade used for adjusting pkl is as follows:
Examples include inorganic acids (e.g., hydrochloric acid, boric acid, phosphoric acid, carbonic acid, 9-bicarbonate, etc.), amino acids or organic acids (e.g., 7-carbon acid, oxyS/*fi/boxylic acid, polycarboxylic acid), etc. Examples of bases include sodium hydroxide,
Potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, etc. may be mentioned, and the buffer solution may be the same as the above-mentioned loose wk soybean.

Examples of the aqueous gel base include natural gums (e.g., tofugacanth gum, acacia gum, kafya gum, ailhund moss, guaiac gum, xanthan gum, locust bean gum, etc.), cellulose derivatives (e.g., methylceta A/loin, Chikara to Boki V) Methyl to cellulose, etc.), Atari/L/acid polymers (e.g., polyacrylic acid, polymeth Atari A/w1
etc.), vinyl polymers (e.g., polyvinylpyrrolidone, polyvinylalcohol, polyvinylmethylether, polymethylene, etc.) 9 Synthetic polymers III (e.g., polysucrose, polyflWcose, d-liwotatose, etc.) , starch, dextrin, betatin, alginate, etc. These bases can also be used as a d1 compound of two or more compounds, if appropriate.

Sutra #! The oil-based ointment for administration can be melted by heating and has an oil-based base K.
It can be produced by uniformly fractionating V clodextrin and the polypeptide and cooling while stirring. Examples of oily bases include those listed above and those of co-workers.

A preservative may be added to the formulation for nasal administration, and examples of the preservative include bafuoquin benzoate ester/%',
Phenol, phenolic products such as creso fi7, clo p-butanol, phenyl ethyl p-alcohol, tD alcohol/L-fit such as puro fin/cricor tv, 41
m1m benzalkonium benzethonium etc. i! i!
sex soap, benzoic acid, sorbin a, 'f' hydrovinegar,
It is possible to use sodium hydrogen chloride or sodium hydrogen oxide in juxtaposition.

The method for administering the intranasal drug A of this Komei is to set the powder-filled formulation V)-White 17 in a special spray tool equipped with a needle, and then insert the needle. One method is to make small holes in the top and bottom of the capsule, and then blow air through a rubber tube to squirt the powder into the nasal cavity.

In the case of liquid preparations, the # agent is placed in a nasal dropper, null-sai-chi, or similar container passed through which such liquids are applied intranasally, and instilled into the nasal cavity or +1! Examples include a method of administering the same amount.

In the case of semi-solid preparations, fill a tube with the preparation and attach an applicator to the mouth of the tube and administer directly into the llI cavity, or use an intranasal insert to take a certain amount of the preparation and administer into the nasal cavity. Examples include methods to do so.

The dosage of Polypede 1f differs depending on the type or disease condition, but the amount of the preparation is solid per dose. l
In the case of +1 drug, it is about 5 Da to 100 Da, and in the case of liquid preparation, it is about 0.05 g? -0.5m, approximately 501 for semi-solid formulations
A suitable range is 1v to 50011g.

The present invention has the following features.

1) Polypeptides with physiological activity that are poorly absorbed in the gastrointestinal tract can be administered through administration routes other than injection, and high bioavailability* (bloavailability) can be obtained.

2) Physiologically active polypeptides can be easily administered without pain during administration.

3) When continuous multiple administration is required, ζ can be easily administered by the patient and home therapy is possible; 34) Cyclodextrin, which is used as absorption enhancer 7, is tasteless, odorless, and has poor durability. Since there is little evidence of mucosal irritation, extremely safe preparations can be produced even after multiple administrations.

In the following, the present invention will be explained and explained in detail, leaving behind the central experimental example. W/Y%).

★Experimental example/ Sa-line male and female (3 or more animals in each group) that had been fasted for 16 hours and had a body electric potential of about 25 ufv) were anesthetized with benotobarbimer, and then subjected to clinical anesthesia. IJourn
al 111' i) harmaceutica)
According to the method described in Vol. 7, No. A, p. 17 (1981), after performing a rounding surgery for nasal administration, a micropipette was used to directly inject the insulin administration solution into the nasal cavity at a volume of O, lsj/kg through the external nostril. After administration, blood was collected from the tail vein over time and blood sugar levels were measured.

In addition, as the insulin administration solution, porcine insulin IOU
Or 20U (approximately 0.2 Da or 0°8Mf),
α-2β- or r-cyclodextrin
0 ■ [corresponding to θ ~ 10th] at pH 7-4, etc. 11! A 0.1 mK solution was used. However, in the case of β-V talodextrin, the saturation solubility is approximately 1°8 g6, so if the concentration is higher than that, it should be administered as a suspension.

As a control, blood glucose levels were measured in the same manner after intravenous administration of insulin.

The results are shown in Table IK. As shown in Table 1, g -9β-
It can be seen that the addition of ° or r-cyclodextrin caused a significant drop in blood sugar compared to the case without the addition, and that insulin was effectively absorbed through the mucous membranes.

Table-1 Blood after intranasal administration of insulin to foot 1j
li wax change experiment iNλ ′″C-DA/-1417 equivalent to 2 da/kg and α-cyclodextrif 511 & (5% equivalent jt) to 0.1
0.1 d was dissolved in physiological Jk saline in the same manner as shown in Experimental Example Z, and 0.1 d was administered into the 4th cavity with a micropipette, and blood was collected from the caudal vein over time to determine the total radioviscosity in the plasma. The blood concentration was determined by keeping it constant. 1 was used as an experiment, and similar experiments were conducted with subcutaneous administration of the same dose and nasal administration without addition of α-cyclodextrin.

The results are shown in Table 2, and it was revealed that nasal administration of the formulation of the present invention markedly increased the absorption of peptides.
4 increased 5 times from JIO% to about 50%.

★Resolution 1,41j rA]'-144 100 μf and a-V Clote Jf String 5~ are dissolved in Q, l- physiological saline-water Y bath, and refreshing example/
An amount equivalent to O, lj/kg was intranasally administered to rats in the same manner as above (the dose of TAP-144 was 100 μf,
kg K), blood was collected over time by tail hunting, and DAP-144 in the serum was quantified by immunoassay. As a comparative experiment, we conducted similar experiments on mice in which 2 days of administration was administered overnight or a preparation containing α-V clodextrin islets was administered intranasally.

The results are shown in Table 3, and it can be seen that the composition of the present invention
By administering the peptide, the absorption of the peptide increases significantly, and the bioavailability for anti-depressants is 20% or more:]7
It is clear that Natsutomo will increase 0% and 3.5 times.

Higashio side/ 5000U of porcine insulin (about zooq) at pH'7.
The mixture was dissolved in a 4-theta isometric phosphate buffer solution, 500 ml of α-cyclodextrin and ~20 q of taloloptanoate were added, and the mixture was completely dissolved, followed by a solution of 1011 It with saline water. Place this in a nasal spray container and spray approximately Q, 1 m at a time.

Implementation fA+, 2 DN-1417200 Cape, Y Nni) -N 200
11Q and β-cyclokistrin 200 cape in purified water 40m? Dissolve and lyophilize into circles. The obtained round dried product was pulverized into a powder having a particle size of approximately 20 to 250 fi talons. Fill 30 ~ of that into No. 4 hard ift nkadese ρ and make a circle. When administering this capsule, set it in a special spray tube with a round needle that makes a hole in the Vτ cell and a rubber bulb to send air, make holes at both ends of the capsule, and then insert the rubber bulb Press to send air and administer the powder into the nasal cavity from the tip.

Higashio side 31 Methylparaben Q, 12m, Globi M Buffben 0, O1
16 ml of pH 7.4 isometric buffer solution containing ★ Ka −
1g of cyclodextrin and 29 of TAP-144
Dissolve M and add methylcellulose (Metrose 90S) to this.
H401) 0. Shin-Etsu Chemical Co., Ltd.) 2001f11r
: Added and stirred well to make a uniform refined steel solution. 100 or more of this book is filled into a nasal pitcher or licator (filled and administered into the nasal cavity).

Tokari natural type LH-RH (in general formula (1), R knee kl
is, R2-Tyr, R3-Gly, R4
-Leu, R5=G1y-NH,)
500M! and α-cyclodakist Vnlf) in a mortar, add the heated and dissolved Funolino 1y, and mix and disperse well. Next, while stirring, Miglio = #812C Daikamito Nobe #
(manufactured by Dyna-Nobel, Germany) was gradually added to give a total concentration of 10% to obtain an oil-based suspension IB agent.

Place this in a container with a dropper and administer □, 11 2C directly into the nasal cavity each time.

5ji! - Example J U-cyclodeginutrin 50III and a-interferon 1oooooou (interferon derived from human leukocytes) were dissolved in physiological saline l@t to form a solution. Put this in a nasal container with a dropper and use 0. 1.1'tllll
Administer intracavitally.

th*Example Dissolve male side serum 2IIIi + gamma-citalodextrin 1v in 10s of physiological saline, add 1100 WI of methylcellulose to make the seminal liquid fCl.Take 0.21 of this into an applicator and i! Intranasal cavity W-
explore.

5ji! - Example 7 Enkephalin If and a-V clodextrin 3f were dissolved in physiological saline to form a solution. Put this into the potion,
Administer 0.2 d intranasally (spray) each time.

Claims (1)

[Claims] A nasal preparation containing a physiologically active polypeptide and V clodextrin.