NL8700416A - PHARMACEUTICAL INJECTABLE AMOXICILLIN PREPARATION. - Google Patents

Description

V.0. 9038 * - i

Pharmaceutically injectable amoxiciilin preparation.

The present invention relates to a new injectable amoxiciiline preparation.

Amoxicillin is an antibiotic of the betalactam family, the therapeutic importance of which has long been undisputed.

Pharmaceutical amoxicillin preparations for oral administration are readily prepared in all known forms, such as, for example, capsules, tablets or other such ingestible forms.

Injectable forms of such preparations, on the other hand, require the use of soluble amoxicillin derivatives and a suitable solvent, which may be water. For this reason, amoxicillin salts, such as in particular the sodium salt, have hitherto been used to obtain injectable preparations.

However, these solutions have limited stability, so it is difficult to prepare them on a mass-produced scale with sufficient purity because the salts will decompose.

In addition, intramuscular injections of the aqueous preparations are painful and irritating to the tissue. It is therefore necessary to add a narcotic to such solutions.

However, the choice of a local anesthetic to make the injection bearable is very limited, particularly in view of the incompatibility of the amoxicillin salts with such types of anesthetics.

For example, an injectable amoxicillin preparation is known which contains benzyl alcohol as a topical anesthetic. This preparation 25 must be injected immediately after preparation. However, this product has a low titer, its total decomposition products and impurity content being high and can reach 10%. In addition, several antibiotic injections must be administered daily to maintain the necessary serum concentration.

Furthermore, while having a pain relieving effect, benzyl alcohol causes local irritations during the intramuscular injection.

In view of these difficulties with the known injectable solutions, in particular the sodium amoxicillin solutions, it was necessary to look for another preparation.

The object of the present invention is to solve the aforementioned problems 8700416 ¾ -¾ -2- by providing a pharmaceutical preparation which is easy to inject, has a higher purity and stability and is able to efficiently treat local pain. during the injection, without causing irritation.

The solution proposed by the present invention to solve this problem consists of a pharmaceutically injectable amoxicillin preparation characterized in that it contains amoxicillin trihydrate, suspended in a suitable solvent.

It has surprisingly been discovered that the local tolerance to an injection of amoxicillin trihydrate suspension is higher than that of an aqueous solution of sodium amoxicillin.

This discovery goes against two prejudices. In general, it is believed that parenteral administration of a suspension should be avoided, given the low tolerance during the injection. Furthermore, parenteral administration is usually only used for products that cannot be dissolved in known solvents. Now this is not the case with the amoxicillin derivatives at all.

For this reason, only the soluble derivatives of amoxicillin have hitherto been used, there being no reason whatsoever for those skilled in the art to be concerned with amoxicillin derivatives, such as amoxicillin trihydrate, suspended in a solvent, especially since the injection of such a suspension a priori should be avoided.

According to a special feature of the invention, the size of the amoxicillin trihydrate particles in the suspension is chosen such that injection of the preparation is possible. It is advantageous when this size is from about 1 to about 25 microns, with about 5 microns being preferred.

In another special feature, the amoxicillin trihydrate concentration in the suspension is in the range from about 100 mg activity / ml to about 1000 mg activity / ml, and is preferably from 200-500 mg activity / ml.

According to yet another feature of the invention, the amoxicillin trihydrate in the solvent is present in micronized form. Micronization is particularly advantageous in that the shape of the resulting particles is fully compatible with the requirements of the injection delivery method.

8700413 * '»-3-

The invention will be explained in more detail by means of the following description of tests and observations / which only serve as an example.

The local pain after a subplantar injection in rats, the local tolerance to an intramuscular injection in rabbits and the bioavailability in dogs of an aqueous suspension of a micronized amoxicillin trihydrate according to the invention were compared with that of an aqueous solution of sodium. triumamoxicillin.

10 Water was used for the comparative study because it is the simplest and also the least expensive solvent. However, any other suitable known solvent can be used without departing from the object of the invention.

The amoxicillin trihydrate was micronized by passing it under a stringent and repeatable condition over a Cristo Jet Mill device. This known technique is described, for example, by G. BOULTiLAY (APGI Symposium Dec. 1984).

The resulting powder was subjected to a particle size analysis, revealing the following granulometric composition: 80% of the particles less than 5 microns in size; 10% of the particles having a size in the range of 5-10 microns; 10% of the particles in the range of 10-20 micrometers.

As mentioned above, micronization of the amoxicillin-25 'trihydrate is advantageous since most of the requirements of the injection method of suspension of the invention can be met.

It will be clear, however, that other techniques, such as, for example, micro grinding or long grinding, can be used.

The purity of the active component after this treatment was examined in the known manner by quantitative analysis and determination of the impurities. The resulting powder was suspended in water only by shaking. The suspension obtained was homogeneous and easy to inject.

Two different slurries were prepared, the respective concentrations of which were 200 mg activity / ml and 500 mg activity / ml 8700416-104- expressed in terms of amoxicillin in anhydrous free acid form.

Test 1: Pain during the injection.

Pain studies during injection of the OFA strain 5 into female rats were conducted according to the E. CELOZZI, V.J. LOTTI, E.O. STAPLAY and A.K. MILLER technique described in J. of Pharmaceutical Methods 1980, Vol. 4, pages 285-289.

The rats' weight ranged from 60-80 g.

The following four preparations were used for this test: - amoxicillin trihydrate / water for an injectable preparation (500 mg activity / ml); - amoxicillin trihydrate / water for injectable preparation (200 mg activity / ml); 15 - sodium amoxicillin / water for an injectable preparation (500mg activity / ml); - sodium amoxicillin / 3% benzyl alcohol (500 mg activity / ml)

Benzyl alcohol was used here as a local anesthetic.

0.1 ml of each of the aforementioned solutions and suspensions was injected into the sub-plant tissue of the leg. The pain caused by the injection was assessed by the rat paw lick reflex test. The number of times the leg is licked after the injection is counted over 3 minutes over a total period of 15 minutes over 3 minute periods. Licking the paw is defined as: licking followed by averting the head or 5 seconds of continuous licking. The results obtained are shown in Table A.

/ y u <·· * f o -5- μ — t * t \

* I

CM | S

in · H S m · v i-l <£> · J · o I CM 0.0 o Φ Ό c aj m p r-i r- 3 1 * 0 o o

O CM O

C <U. rP.

«Θ 'p .....- - I. - - p c

ld (U

Ρ M

si C cm

3-p 0) -1 cm

• P r4 Ρ I * Λ ^

3 (Tl 1-4 o O O

0) CC

• Ρ © -P __._____; __ -P iP g a <e ai g ro cn "3 *

η IO

C ip C CQ H O O

«C -P ld <Ü _____ -P> -------- ----

0) C

p nj e „

4 ij a 10 10 1-4 rP CM

d id tJ I · · · * p ai o co r ~~ o o o a c ό -w ld r4 $ 4 _____ m i-i © © ------- ft Ό ft <ja ό w 3 -Η * o cn

H-I (0 £ -n cm CM CM

© · Η 1 in · ·

rd O p O H O O O

c l a L ------ • n ft z in o cm σι i-4 in. © «-; ---- 53 - Τ) -, ¾ C P C Ρ o -PO) -p cu

J P r — I 4- * i — I -P

a> ip ld i-4 fO

+ P + i-4 * P !? Ρ 3 id o o o S Bi i -p Ό · ρ Ό σ> o x p x p t3 ip o o © oa) tp P Ή g © g © a) id id id η id η c

Id a) Z lp lp> P 0)

z H> 1 T3 -P Ό -P P

η a) n pp pp φ a> -pac © co cu cn · ρ c -ρ · ρ © ma) © © Ό -ρ cn ip ja cn Ό ίο Ό H a) H -PO) · Ρ © Η ρ Α · Ρ # co a Bi «• Ρ 0) Ο co Ο Ο +>

Ο Ο · Ρ pip Ρ · Ρ C

• ρ χ γρ ο Η ϋ g id χ η ο g · Ρ · ρ id ο g g g cm g m

g 5 cm <D © II

<CM O + C3 + '2 8-? p P f i "t / G V · 5 '«> -6-

As can be seen from the results obtained, the injection of a sodium amoxicillin in water solution, especially during the first three minutes, is painful. After this, the pain subsides. On the other hand, the injection of trihydrate / amoxicillin suspended in water, whatever its concentration, is painless, while the obtained score can be fully compared with that of a local anesthetic.

Experiment 2: Tolerance of intramuscular injection.

The aim of these tests was to investigate muscular irritation caused at the site of injection and the cause of lesions over time.

The trial was conducted with 12 adult New Zealand rabbits (froxfield breeding farms, Hampshire). The rabbits were divided into three groups of four; the dorsolumbar area was shaved and they each received six simultaneous intramuscular injections into the spiral-shaped muscles of the sacrum, of 0.5 ml of the following compositions: - water for an injectable preparation (E) - 3% benzyl alcohol (B) - sodium amoxicillin 3% benzyl alcohol (C + B) 20 (concentration of 200 mg activity / ml) - trihydrate amoxicillin / water (200 mg activity / ml) (A + E) - trihydrate amoxicillin / 3% benzyl alcohol (A + B) (200 mg activity / ml).

The three groups of rabbits were sacrificed 2 and 14 days after the injections, respectively.

The injection sites were then subjected to microscopic examination. The lesions were measured, with a score according to their intensity as follows: 0: no change 30 1: very mild condition 2: average condition 3: clear condition

The individual results of the microscopic examination are shown in Table B.

6700416 -7- «ί- <*

After this, samples typically taken for each injection site were paraffinized, cut into 5 micron pieces, stained with hemalum phloxin saffron, and at a normal, histological level. investigated, summarizing the results in the following Compare-5 Table C.

8'70 3 * 1 3 -8- 0

YOU

"M

β 41 ΗΟΝΟΠ o o N H O NNNNfl

<0 ~ t • u UI

c Ui • »4» Ή c <yy »1« · «« · ► «* · <·« * ······· · «·· · * ·« · «« «« S 'w Ό « gj *, ^ «t« β »in« * οβ λ * · »μια T-. «Cv ™ u» cn te a «** ^ xoxox cx $ xxx ooxxo c κ xxx χ U) TI S g., _, * J—. £ β CO« 2 K fO OO · Γ> CV · 'j AIDOlfllfl SS £ «" * ^ § Ή g «1 X 'g CV Ψ * g ι-t CV« · * «4 S * S x * 3 α 5

Sw o c x 0 »*

+ J

• H

0)

YOU

• H

«§ • 2 nnnrtw h ^ nnn o ^ nno h * (nn« 4

X UI

o αν * H / "i J C ••« «•• x - <· <——-» - <· - «··« «xxxxxxxxx χχχχχχχ- ·· ® 4) ca & <

CQ T5 W

flj <m o β irt o cn ^? «-T *» in »rt® cv -g * η λ m« cox ητίΝ ^ Ν <u B trt + xxxxx (β xa XXX rv q χ χ χ o ® XX xxxx _ a δ «ri IflNOOW {. · Π n SN S c O CV «= ® CV ® W Γ» 0 la 'l'V Τ4 * 4ψ * ψ4ψ4 .p, SrtH. {5, * 4 «4 * 4 J, H» 4 wts 0: -4- .4 -π so »-3 oo ccc o 1xo ooaxx *

YOU

• w

Onion

4J

• 4

ONION

e c a>

S S ί * v * 4 o cn * 4 πιμνπο rtnnih HnntiH

w x -a asm

• 4 HO

<r - “4 g ^ μ cn«

O) «E C

g ‘5 c« * rt S «e ^ SS - λ m £ ί cn * 4« v «at« u 2 B x x x O x x o x x x x o = x x x x x c x x x x x o »x a o

Lcn o a o ex o o · * © λοιαχ * nomno N CM fUftIN HWffM Cv «4 * 4« 4 5J1 βϋ ^ χι ^ χ ^ χβββι ^ * ^ mm c

• M

4> Uf β S woe UIBB IUBB

1 c ♦♦♦ *! «♦ ♦ ♦ ® 14» ♦♦♦ aui ♦ ♦ ♦ § «<« << U <<U << UBU1 i. (t) W] * 870 0 415 * -9-- *

TABLE C

histological examination - comparative results muscle fiber muscle fiber cellular fibrosis bleeding total degenara degenara infiltration tie

GemicronisegrA ampx-i <». · <N, i no -i watey fip ^ for injectable preparation) J e 2 U, 1m (M) 0/4 4/4 (1-2) 0/4 0/4 J ♦ 5 3/5 (2-4 2/5 (1-2) 3/5 (2-3) 0/5 1/5 (1) J ♦ 14 2 £ _ (3) 2/3 (1-2) 2/3 (3), 2/3 (2-3) 0/3

Total 9 / 12_4 / 12 9 / 12_2 / 12 1/12 25

Micronized Amoxicillin + Benzol Alcohol J ♦ 2 3/4 (3-4) 0/4 3/4 (2) 0/4 3/4 (1) J + 5 4/5 (3-4) 3/5 (2) 4/5 (3) 0/5 0/5

You 14 1/3 (3) 1/3 (2) 1/3 O) _ HL · 2 £ 1_

Total 8/12 4/12 8/12_ 1/12 3/12 24 sodium salt + benzyl alcohol J * 2 3/4 (3-4) 0/4 3/4 (1-2) 0/4 2/4 (2 -3) J ♦ 5 5/5 (3-4) 5/5 (1-3) 5/5 (2-3) 0/5 2/5 (1-2)

Your 14 3/3 (2-4) 3/3 (2) 3/3 (3-4) 1/3 (3) 0 / 3_

Total 11/12 8/12 11/12 _1 / 12 _4 / 12 35

^ nsYlalcohaL

J + 2 4/4 (3-4) 1/4 (1) 4/4 (2) 0/4 3/4 (1-3) J + 5 4/5 (3-4) 3/5 (1 -3) 4/5 (2-3) 0/5 1/5 (2) J * 14 213 f31 m. <SL IÖJ2L 2 / 2_

Total 10 / 12_6 / 12 10 / 12_ 2 / 12_4 / 12 32 water'fip ~ 771-2 / 4 (1-2) 0/4 2/4 (1-3) 0/4 1/4 (3) Y ♦ 5 1/5 (3) 1/5 (3) 1/5 (3) 0/5 1/5 (2)

You 14 1/3 (1) 1/3 (1) 0 / 3__ ~ P / 1-. ° / 3

Total 4/12 2/12 3 / 12_ 0/12 2/12 11 (i) number of tuna with lesion (ii) number of rabbits examined (iii) intensity of lesion 8700416 -------- g -10- Γη Tables Β and C classify the preparations by the most irritating to the best tolerated. This classification is as follows: sodium amoxicillin / 3% benzyl alcohol, 5% benzyl alcohol, mononized trihydrate amoxicillin / water for an injectable preparation, and mononized trihydrate amoxicillin / benzyl alcohol, water for an injectable preparation.

Table C in particular shows the poor results of benzyl alcohol used alone or as a local anesthetic with sodium amoxicillin solution.

Experiment 3: Bioavailability

The bioavailability of an aqueous suspension of mononized amoxicillin-trihydrate compared to an aqueous solution of sodium amoxicillin was examined by conventional tests.

The study was conducted using sodium amoxicillin, prepared with 3% benzyl alcohol as solvent, and the trihydrate form in an aqueous suspension for an injectable preparation on dogs, on the one hand.

6 beagle dogs (3 males - 3 females) weighing 10.8 kg - 14.5 kg were administered by the intramuscular route (dose: 50 mg / kg) the following two preparations: - sodium amoxicillin / 3% benzyl alcohol 2S - amoxicillin trihydrate / water for an injectable preparation.

Serum concentrations and urinary removal were determined microbiologically relative to a standard range using the disc method (Sarcina Lutea ATCC 9341 strain).

Blood samples were taken at the following times: 30 minutes, 1 hour, 1.30, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 32 hours, 48 hours after injection.

The urine was collected from 0-6 hours, from 6-12 hours, from 12-24 hours.

Table D shows the values of serum concentrations as a function of time for each of the formulations tested.

Table E shows the values of urinary removal "700413" »-11- as a function of time for each of the preparations examined.

Table F shows the areas under the serum concentration-time curve for each assayed preparation.

These results show that the serum peaks are higher and earlier in the case of the preparation of sodium amoxicillin in solution, whereas in the micronized preparation there is a persistence of the serum concentrations (see Table D).

A minimal inhibitory concentration threshold at 5 mcg / ml was determined arbitrarily but in accordance with conventional inhibitory antibiotic concentrations.

Table D shows that the drop in serum concentration to the minimum inhibitory concentration for the sodium amoxicillin is reached within 5 hours and, in the case of the micronized preparation, within 10 hours of administration.

This quantitative view of the concept of bioavailability shows Tables E and F that the values of total urinary removal as well as the areas under the serum concentration-time curve do not differ statistically.

Urinary removal is significantly higher for 6 hours in the case of sodium and in the case of the micronized preparation, starting from the sixth hour, significantly higher, with the 24-hour elimination not significantly different. From the significant removal over the 12-24 hour time interval observed in the case of the micronized preparation, it can be predicted that the urine concentrations will persist beyond 24 hours.

«70 0 416 -12- · * ** v- 1 i! j - a ί «s a s a a a ^ · *%« · t «'· J o o o o o o o {V v v« Ι β n t · ^ n? u jdöeöóed j ο ο noee 2 · * # * * · # * »* {N f4 NN Η τ <tl σι ί -« «*« ο »« ο 5 ^! ··· * .. ♦ J w 4f 4τ η Ν w η α> ι ΐ Q j Ν β β »Ν Ν 8 ι- Η jt η t β ^ t α

® Ν · β β β ^ Ν ΙΟ I η Ν α Ν V Ν S

C β O 'Ο Ο * Ο Ó Ο Ο I 4Τ β 10 β (Ó β 4β U! Β

ε Β α β f4 rt ΙΟ 0 I Ν Β Β V ir t S

° 5 2 ® Ν η fi Ν f4 Ο f4! Ο β e f4 * β) · «D

ν ο J τ4 α η oeor ^ ocM η ινοβννν ν W Ο ^ Ν S Ν β> Λ Ν (0 I CD Ν NT fi Ο Η ¢ 31 ° I ^ rl tl rl rl «Η dj T <V®« o fl O »CO I ttt β β o δ * · · ί · ~ sss ft S ft s '! A' 5 saa 'a 0 I e Q oooooo tn ι e» co * »m ο δ ft S gs' s? G 5 l · a 'aaaa' OOOOO o BS to OO o CM «O δ" sssss' ft s', j * aa 'a' ^ s in ooo ooo β! Cm mn as η μ n o 'S3SSSSS s ί · ^ ·· Ν ·· 's

f4 f4 I

S β f4 η β) N β I 0 f4 ΙΟ η N B

<Ü * · · · · I · · · · Λ o »2 Q 2 ^ ^ © i t n t N n o’

u * 4 tl rt rt t4 ti I f4 f4 f4 f! fl S

«^ I

• ft σ O) __ I

V X Z ZXXU.U.U. ι _ _ m ~ j X X X U. I U.

ft!

Z »4 N n t Λ β« Β N B 0 0 B

*

g! S

C I I) u if, f4 H * S ü <ö 2 - i <- · «ft 2 S 3 <0 B-I-I T3 · C ft. r-l U 3 u <0 · o 2 S «(O -ft .3 .3% e -rt fci Ό ·% jg -. s 15 51 3

£ * 1 - j. It I

u co + a v '870 0 4 1.6 -13-: l. α »^ β 5« ^ n i ^ ^ σ »e« o ca w r * β η n n rs n ΐΜίοαηβΜ n * x s * i s δ 8 s i s g 5 4 s s s α! ^ c co ι a 3 ¾ t si n β ttnin «hnomo 3 β * ♦ · * · O ft I ·« ·! · «* η η β β β η $ β ι ι * * 4 m and ψ * η ω -4 «η ηι δ ιβ ο 3 ι ν ^ ^ a ν ο ο S ο t τ β <r η η η ι« η η «η η η ά ι; 0 #} ®, 3¾ dl β I · ί4> -Ι

, Jj CO I Μ (U

. T. Η 3 ί 3 § 3 ίβ MO I 3

3 c 3 S {CH

m -it <β! -4 9-4 2 g c n} ii} ι a> m J w> 4.-4 · & ® {

ϊ I

~ (ΑβτΐιΑιΑο β ι no> co co as o> β * * · «* ^« ο cm 3 ι 4r «em« * o- «<· cu b * ® cm o in © ο o * 4 ι a cm os cm cn m © 3 Ü, jn eg η T, „« ι <r ^ 1 · <? - ΙΛ j

^ g-aMMa ^ ior ^ i ^ ocB ^ vcoM

(u · Η · * * ♦ * · * I ♦ * # · # · · ïïf- (© «4 05 CM * 4 Ο I Ο Η Π Ο Β N <0

Vr4m v4t <ao »r« iaacDai ® ^: a s »

Ol I

a g * I

ω α 3- N rt ΙΛ fl q g co ι 4r r> o cm cm ca 9 5 η r> «rv ^ 3oo f <ococ» ncMe »^ 9 Ό ** * ··.« · · I *. . , · · · Ü; β n in n o n «4 ι η is n <e n cm

<·· 3? C * 5 4 I, n N rl N N N CM

* 3 | !

® Ή I

• H CM 1¾ I

01 ο ι J0 R, 1 »oocMOcaaBeiar> cp <vtAii9aa ε« O 01 © r4 f * U> I CM ^ U9 Q <0 09 5 t N Λ in 4 nn ι tn ο n is N * »CM I Η H t, r, rt H rl *} .Ξ es »η η a <sr * t κ a cm c * ^ 9 ** ^ N 4 o 4 a>» (Ο I t4 C3 CO 03 CM O ^ to · * ... *>, * · .. ·...

c co Q n in a et in ι ta ea go 05 t * r «. o H USO tXl 9 «4 <-4 * 4

u e J

«Η Ή C

3 (Η I

3 β I

ο ο β »r *» ^ ο ι m o 0> ^ ο o ιοί «4r ** in r> * r ** v ι« ο cn ο T- cm r * i i? o «n« ^ ίο ra ι to in © <o r * © to

° 5 9 CO Cl CO CM CM I

3 "j 2" j 1 "H * H Μ Β T Λ β 3 · 2, § £. I; rc CM 9 9 «η © |

• B §; I

<a 1 c «c! m e * j 2} <a ”-μ i J (0 -4« 1 m, -4 {-4-4 0

β J, --4} fi * U

w go, 2 o -o o -w -η ι u · **> * a.. Ü x »-3 x .c o" ο ι s O - »4 i * a *» 1 "I u ο. Ο * ω a + s tr 8700416 -14-

TABLE F

"Preparations

No. animal

Sodium trihydrate 1. 168.80 120.89 2. '174.72 151.11 5 3. 173.45 156.15 4. 193.70 172.79 5. 140.97. 129.19 6.117.97 127.54

Average 161.60 194.94 From the above results, it can therefore be concluded that the pharmaceutical composition of the invention can also be successfully administered to humans.

In this regard, it is not necessary to describe the pharmacological properties of such a suspension here as they are those of amoxicillin trihydrate, the effects of which have long been known in themselves.

8 “3 ƒ * Λ · - -». "· / Y U i

Claims (6)

Pharmaceutically injectable amoxicillin preparation, characterized in that it contains amoxicillin trihydrate suspended in a suitable solvent. Pharmaceutical preparation according to claim 1, characterized in that the particle size of the amoxicillin trihydrate in the suspension is chosen such that injection of said preparation is possible. Preparation according to claim 2, characterized in that the particle size of the amoxicillin trihydrate is in the range from about 1 to about 25 micrometers and is preferably about 5 micrometers. Pharmaceutical preparation according to any one of claims 1 to 3, characterized in that the concentration of the suspended amoxicillin trihydrate is in the range of 100 mg activity / ml to 1000 mg activity / ml, preferably 200 mg activity / ml - 500 mg activity / 15 ml. Pharmaceutical preparation according to any one of claims 1 to 4, characterized in that the amoxicillin trihydrate is present in the solvent in micronized form. Pharmaceutical preparation according to any one of claims 1 to 5, characterized in that said solvent is water. ______ -A 8700 "; ·