NL8600299A - COMPOSITION FOR RECTAL ADMINISTRATION OF CALCITONINS. - Google Patents

Description

, * VO 8028

Composition for rectal administration of calcitonins.

The invention relates to a composition for rectal administration of calcitonins. More particularly, the invention relates to a new composition which provides excellent rectal absorption of calcitonins.

It is known that numerous injectable drugs are not readily absorbed from the gastrointestinal tract due to their low lipophilic character and / or ionization at physiological pH in the lumen. However, injections often cause pain or muscle contraction and are not suitable for clinical use.

Furthermore, even though some antiobiotics with good absorption properties are administered orally, an increase in the dose or the number of administrations is often required due to the fact that the concentration of the drug in the blood decreases in an extremely short time to an undetectable level. In that case, intestinal bacteria undergo bactericidal or bacteriostatic action through unabsorbed antibiotics.

Consequently, change occurs in the gut bacteria stage, which can result in unwanted clinical problems.

Furthermore, numerous compounds are known which are enzymatically degraded in the gastrointestinal tract by the digestive juice when administered orally.

In view of what has been said above, numerous attempts have been reported in the literature to improve the bioavailability of these water-soluble drugs.

In the investigated Japanese patent publication (Kokoku)

No. 57407/83 discloses a base containing at least one compound selected from fatty acids of 8-14 carbon atoms, leucic acid and non-toxic salts thereof for rectal administration of β-lactam-30 compounds and high molecular weight peptides.

In Japanese Unexamined Patent Publication (Kokai)

No. 149209/80 has disclosed a composition containing a fatty acid of 8-14 carbon atoms or a non-toxic salt thereof for rectal administration of an 8-lactam compound.

♦ v 9 * -2-

In Japanese Unexamined Patent Publication (Kokai)

No. 80314/82 discloses a composition for rectal administration containing at least one carboxylic acid selected from fatty acids of 8-14 carbon atoms, leucic acid or non-toxic salts thereof in the case of an active ingredient * consisting of an aminoglucoside antibiotic, a polysaccharide, a low molecular weight peptide (molecular weight of 4,000 or less), a mercaptopurine derivative, a nucleic acid compound or the like.

Regarding calcitonin preparations, there is a report in 10 "J. Pharm. Sci. 78., 1366-1368 (1984)" that tests were performed with rectal injections containing [ASU '] -alcalcitonin, which is a derivative of calcitonin and polyacrylic acid gel, to obtain 0.8% bioavailability versus intramuscular injection.

Japanese Unexamined Patent Publication (Kokai) No. 118013/81 15 discloses a composition for rectal administration containing a calcitonin in which enamines, N-acylamino acids, beta, imidazoline amino acid derivatives, N-acyl peptides or amino acid esters are dispersed to aid absorption.

It has been found that the calcitonins as such are poorly absorbed through the rectum, but are satisfactorily absorbed into the blood through the rectum upon addition of capric acid or a non-toxic salt thereof. The present invention is based on this finding.

The invention thus relates to a composition for rectal administration of calcitonins, which contains a calcitonin as an active component in combination with capric acid or a non-toxic salt thereof.

Fig. 1 shows the effect of the addition of various fatty acid salts on the plasma level after rectal administration of calcitonin solution.

Calcitonins as referred to herein include natural calcitonins and pharmaceutically active derivatives. They mean peptides with at least hypocalcemic activity. Preferred calcitonins for use in this invention are eel calcitonin, [ASU 'Jaal calcitonin (common name elcatonin), salmon calcitonin, [ASU1 * 7] salmon calcitonin, pork calcitonin, human calcitonin, [ASU *]. * · ... «1 -3- human calcitonin, etc. (See British Patent Nos. 1516947 and 1590645.)

A single dose of these calcitonins is about 0.1-5000 degrees / kg. They may be present in the composition in a desired amount.

The non-toxic capric acid salts used in this invention can be any pharmaceutically acceptable salts, preferably sodium caprate.

The additive, namely capric acid or a non-toxic salt 10 thereof, can be used alone or in the form of a combination of two or more thereof.

The amount of capric acid or non-toxic salts thereof added to the composition is 0.1-25 wt%, preferably 0.5-10 wt%.

The preparation of the present composition for rectal administration using a base for rectal administration can generally be carried out by adding capric acid or a non-toxic salt thereof to the base to obtain a homogeneous dispersion and then the calcitonin add 20 to make a homogeneous dispersion.

The order of addition is not necessarily exhaustive and can be chosen as desired. If necessary, the compositions of the present invention may also contain other additives such as antioxidants, stabilizers, preservatives and the like.

Accordingly, it is preferable to increase or decrease the amount of capric acid or non-toxic salt thereof to be added, depending on the additional amounts of the active component and the third component previously determined. In that case, the amount of the acid and / or its non-toxic salt in the total composition (a usual base + active component + capric acid and / or a non-toxic salt thereof + a third component) can be increased or so that the amount is 0.1-25 wt%, and preferably 0.5-10 wt%.

When a water-soluble base is used as the base for the composition for rectal administration of this invention, capric acid and / or a non-toxic salt thereof is added * 4 Γ -4- in an amount of 0.1-25 wt %, preferably 0.5-10% by weight. When an oil base is used, capric acid and / or a non-toxic salt thereof is added in an amount of 0.1-25 wt%, preferably 0.5-10 wt%.

The composition for rectal administration according to this invention can be used in a dosage form such as a liquid, a solid, a suspension, an ointment, a soft capsule and the like.

The base in the composition of this invention, to which capric acid or a non-toxic salt thereof is added, is preferably an oil base or a water-soluble base. Examples of the oil base are vegetable oils, for example peanut oil, olive oil, corn oil, castor oil, cocoa oil, fatty acid esters of glycerine, such as hard fat (fatty acid triglyceride), Witepsol (Dynamite Nobel Co., Ltd), FARMASOL (Nippon Oil & Fats Co., Ltd.), SB-Base (Kanegafuchi Chemical 15 Industry Co., Ltd), ODQ, (Nisshin Oil Mills, Ltd.), etc., and mineral oils, such as Vaseline, Paraffins etc. These can be used alone used or in the form of a mixture of two or more thereof. Examples of water-soluble base are distilled water, polyethylene glycol, propylene glycol, glycerine, etc.

Calcitonins can be added as a mixture with the oil base or a water-soluble base. Calcitonin in the form of an aqueous solution can be poured into a hollow type solid oil base to obtain the composition for rectal administration.

Any known additives, such as surfactants, preservatives, oils, etc., may also be added to the base in the rectal administration composition of the invention.

The non-toxic salt of capric acid which can be used in this invention is generally solid and preferably has a particle diameter of 0.15 mm or less.

The invention is further elucidated on the basis of the following examples, which have no limiting meaning.

Example I

Study on the rectal administration of calcitonin to rats 0.103 mg (5000 units / mg [ASU1'al-calcitonin (common name elcatonin)) was dissolved in 1 cm distilled water and the - '' Λ =) -5 solution was added 10 mg of fatty acid salts (sodium salts of fatty acids) added as shown in Table A to obtain a composition for rectal administration. Each solution was administered rectally to male rats of the Wistar breed (body weight: approximately 5 250 g, a group consisting of 4 rats), which had been fasted overnight and anesthetized with sodium pentobarbital at a dose of 100 units / 0, 2 cm3 / rat. After administration, the anus was closed with Aron Alpha to prevent leakage.

0.5 cm -1 of blood was drawn from the jugular vein at 5,10,15,30,45, 60 and 90 minutes after rectal administration. The blood samples were centrifuged at 2500 rpm for 15 minutes. Then the concentration of elcatonin in the plasma sample was determined by the method "Enzyme Immuno Assay (EIA)" described in "J. Pharm. Sci. 74, 300-30.3 (1985)".

The results of these tests are shown in Table A below.

5 v "0 ί 0 9 -6- 9 - z c Ή g in w m - in m ·. S V» «· o i — i cn η <n in cn ni o ö

• H

g in in o o O cn τι * ‘in“ ro H o

Cfl CN i — i i — i ö Ή g m m m o o in m O Ν 'co cn

«3! H rp CN CN O

ro u

N

2 ö

g * H

wg in in o O m • te · »« t «· s ns o oho o r- · og ΓΟ H CN \ QN * ro cn (Ö ______________________________________ ft + j Ö CU Η Λ rj g in mo mm *» * c in * * or * - cn o AH cn cn o co co h cn h

H

H -P

0) (0 C

Λ Μ H

(3 + j g £ Ö m o m m in ai * * «* * o o cor-icfl cn o o c η h m cn <n o o_______h_______ ___________________ • 5 in m o in o g * * * * * o o r- h o o m Η Ν 'o co r ~

H

H

c -P -P <U

Φ i + ji (ö iii nj cn ö> d -. G nj g cd g -PS -P g cd Cn c <Urt »3 cd 3 h 3 cd 3 cd 3 -p <u A MO -MO Η> i H <d H Cd -AM 0 H 3 H MM MM MM MM M -HG>

Η Ν'- "-P ft -P ft -p ft -P 3 -P M CU CU

CU .p cd cd id cd cd cd cd cd cd> ι Φ 0

+ i O) Cü ö u c u e H C S O -P

cn> __ <u

S

(0 <U -P

cn -P c · cd

C -A Λ M

<U CU CU C C 'V

H> G O CU ro

cd <U 0 + J CU S

• p -H a cd υ O VS ü o

CU ü O H O CN

O cd O <U H

—PO

V - 'v'

J

-7-

The result is shown in Figure 1, wherein - "O" * shows the result without additive (blank),-,- -na trium aprate, sodium aprylate r -Δ- sodium caprate. sodium laurate and -O sodium myristate.

From the results obtained, it is clear that sodium caprate is particularly suitable in compositions for rectal administration of cal-citonins.

Example II

Study on rectal administration of an aqueous calcitonin-10 solution to dogs of the Beagle breed.

2.0 mg (5000 units / mg) of elcatonin was dissolved in 2.5 ml of distilled water. Sodium caprate was added to the solution at various concentrations as shown in Table B. Males of the Beagle breed (body weight: 9-11 kg, a group consisting of four dogs) were fasted overnight and each of these solutions was administered rectally in a dose of 0.05 cm3 kg. 1.0 cm blood was drawn from the forelimb vein at 10, 20, 30, 60, 90 and 120 minutes after rectal administration. Each of the blood samples 20 was centrifuged at 2500 rpm for 15 minutes. Subsequently, the concentration of elcatonin in the plasma sample was determined by the EIA method. The results are shown in Table B.

- '8 - g • Η

g CO VO TH

»I« ^ o o n * cn m Ν 'CN'

iH

♦ c

• H

g CO CÖ VO CN CO

«P n O O H vo ΠΊ VO N · σι

G

H

r 'g CN VO CN CN Q CN

ng »·" · »** · *» v 0 o HiNp'inom

\ VO rH

3________

B

G

J * H

g g in v cn in -) n »ÜJ« · »<. * »» - x, (8 O CN N * in ιΗ ΙΟ Γ "

rH m ~ rH iH t-H

a _______: ___ 4J ’

CD G

G · Η ep g n rn in ιο in in _ C λ »s r» - rt- **.

S o vo co «* © r * cn

O φ CN CN CN i - | (—I

ê a ------- s · -U G.

G · Ή

01 g CT> VO 'VO O CN CD

O λ r * λ. *. ·. n § O O Ν ’(—1 CN UI cn Ό rH rH <H Ν 'Ν' r— |« Η

G

cd, i, (β 4-1

Ifl CU 0

dP c #> dP dP Λ3 <JP

(βίβ H CN ^ 00 O O

t-4 o cn n 4-1 δ G G p ai οι · ιΗ

οι oH

G S + i

-H 0 (tJ

r4, O · G H '0 "'" '......... ...

• P

§ g 1 £ c

0 G C

cn m 0

ai e 4-J

H CU g O

Λ H Q <

4-1 4-1 g CU

O ü O

ft «V o -9-

Example III

Study on the rectal administration of an aqueous calcitonin solution to rabbits.

0.113 mg (5000 units / mg) of elcatonin and 400 mg of sodium caprate were placed in a 10 ml measuring bottle and dissolved in distilled water, which was added to a volume of 10 ml. There was thus obtained a solution containing 50 units / cm 2 of elcatonin.

Male rabbits of the White New Zealander breed (body weight 2.5-3.0 kg, a group consisting of 3 rabbits) were administered elcatonin 2.0 solution rectally at a dose of 10 units / kg. Blood was drawn from a vein in the ear before administration and 1,2,3 and 6 hours after administration. These blood samples were allowed to stand at room temperature for 30 minutes and then centrifuged at 3000 rpm for 10 minutes to obtain serums. The serum calcium concentration was determined by atomic absorption.

As a comparative test, a blank preparation containing 50 units / cm 2 of elcatonin without sodium caprate was prepared, and that preparation was administered and the serum calcium concentration was determined by atomic absorption.

The results are shown in Table C. The decrease (%) of the serum calcium concentration was calculated by the following equation: p Co'Gt R = _ x 100 co where R means the decrease, C means the calcium concentration for o administration and the serum calcium concentration means at any interval after rectal administration.

Table C

active Decrease in serum calcium (%) component - * --- 1 hour 2 hours 3 hours 6 hours 30 elcatonin -——----- 10 units / kg 22.6 20.1 15.3 3.4

? V

-10-

Example IV

Study on the rectal administration of an aqueous calcitonin solution to rabbits.

0.271 mg (2000 units / mg) salmon calcitonin and 400 mg sodium

O

5 caprates were placed in a 10 cm measuring bottle and dissolved in distilled water, which was added thereto, to give a volume of 10 cm 2. There was thus obtained a solution containing 50 units / cm @ 1 salmon calcitonin.

This solution was administered to rabbits in the same manner as in Example III. The results are shown in Table D below.

Table D

active component decrease in serum calcium (%) _ 1 hour 2 hours 3 hours 6 hours 15 salmon calcitonins 25.7 22.3 17.6 5.1 10 units / kg

Example V

Study on the correct administration of an aqueous solution of porcine calcitonin.

8.56 mg (60 units / rag) pork calcitonin and 400 mg of sodium caprate were placed in a 10 ml measuring bottle and dissolved in distilled water, which was added thereto, to give a volume of 10 cm 2. The resulting solution contained 50 units / cm 2 pig calcitonin.

This solution was administered to rabbits in the same manner as in Example III. The results are shown in Table E.

-! /; -11-

Table E

...... "_” ^ ”” '} active decrease in serum calcium {%)! Component if pig- 1 hour. 2 hours 3 hours 6 hours calcitone -------— -. , n. - 18.4 14.5 9.5 2.3 5 10 units / kg

Example VI

Preparation of calcitonin suppositories 9.8 g of Witepsol H-5 (manufactured by Dynamite Nobel Co. Ltd.) was melted at about 50 ° C, followed by the addition of 0.2 g of sodium caprate with a particle diameter of 0.15 mm or less. Stirred well and dispersed homogeneously to give the base.

Then 4.51 mg (5000 unit / mg) of elcatonin was added to the base and dispersed homogeneously. This dispersion was formed into a 1 g suppository mold. The amount of elcatonin in one put-15 pill was 2000 units.

Example VII

Preparation of Calcitonin Suppositories 9.8 g of Witepsol H-5 (manufactured by Dynamite Nobel Co. Ltd) was melted at about 50 ° C, followed by the addition of 0.2 g of sodium caprate with a particle diameter of 0.15 mm or less.

The mixture was stirred thoroughly and dispersed homogeneously by an ultrasonic treatment. Suppositories were then made into a 1 g suppository mold. Hardening by cooling and a central cavity was drilled from the top of the suppository 25 using a 3.2 mm diameter drill. 100 µl of a 3 'aqueous solution of elcatonin (2000 units / 0.1 cm) was placed in the cavity and the opening closed with said base material to obtain a hollow type suppository.

Example VIII

30 Study on the rectal administration of calcitonin suppositories to dogs of the Beagle breed

Each of the elcatonin suppositories prepared according to the method described in Examples VI and VII was administered rectally to males -12- * 5 ^ of the Beagle breed (body weight: 10-11 kg, a group consisting of 3 dogs), which they had been fasted overnight. 2.5 cm of blood was drawn from a forelimb vein before administration and 10, 20, 30, 60, 90 and 120 minutes after administration. Each of these 5 blood samples was heparinized and centrifuged at 3000 rpm for 10 minutes to obtain a plasma. The elcatonin concentration in each plasma sample was determined by the EIA method. The results are shown in Table F.

-13- ί.

s • Η ε „LO r — i Ο CN ^ ^ χ— {

C

♦ Ρ-Ι s r »00 *> Ο 3 * u1 σν η S --- Ο Ν 3 a3 W τ4 S cm αο« J 'SO in ΐ3 03 νθ Λ

It "-

a

ρ 0)

a

Gco tn C · Η ~ ü s O ^

CM CM

(DO

H <3 P_____ 3

YOU

P

b 3

CU

M ü 3 ΓΟ

<u g -h * CO

P o S VO «ti o Λ <N 03

tl I O

<U CM

3 • H .. - —- '

G

0

P

«S 3 O Ή r4 B Η Π m« - 13 r-i

O M1 O

. i — l

iH

Ρ · Η

G A H H

δ P> H

3 ®. _> a s * s 2 s ® ® ^ O 3 <1> ® O · Η Λ ®

3 P P

<u -h o y> P o o ® O> o • HP> P 3

O O

(¾ Ή <ü ___

Claims (4)

Composition for rectal administration, characterized in that the composition contains a calcitonin as an active component and capric acid and / or a non-toxic salt thereof as a means of promoting absorption. The composition for rectal administration according to claim 1, characterized in that the content of capric acid or a non-toxic salt thereof is 0.1-25% by weight, based on the total weight of the composition. The composition for rectal administration according to claim 2, 10, characterized in that the content of capric acid or a non-toxic salt thereof is 0.5-10% by weight, based on the total weight of the composition. 4. A composition for rectal administration according to claims 1-3, characterized in that the non-toxic salt of capric acid is sodium caprate. c