DE1915191A1 - Suppositories - Google Patents

Description

Soh / Gl K 893

Kyowa Hakko Kogyo Oo., Ltd. * lokio / Japan

Suppositories

The invention relates to suppositories. In particular, relates they focus on a process for the manufacture of suppositories that contain a mixture of antibiotics. Most notably The invention relates to suppositories that contain a combination of macrolide antibiotics and broad spectrum antibiotics contain. These suppositories are dasu in £ age, the blood with the administered antibiotics to be enriched to a high degree.

The contents of the blood on dom administered drugs are in terms of the therapeutic effects of

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Antibiotics essential. Are antibiotics by the oral route administered, then they get through to the digestive tract into the blood and are distributed through the organs. An increase the antibiotic content of the blood is an indication that increased therapeutic effects are achieved can be.

The orally administered antibiotics cannot get through the Digestive tract are absorbed, then they will generally administered intramuscularly or intravenously, which has the consequence that the distribution of the drug over the takes place throughout the body. Oral administration of drugs is difficult or impossible as a result of the The disease to be treated can be caused by the disease, then the drugs are delivered rectally in the form of suppositories. sitorien administered to achieve the desired systemic effects.

The aim of the invention is the preparation of suppositories, which to be able to supply the blood with a high content of antibiotics which are included in these suppositories.

The invention also provides a method of manufacture created by suppositories, which cause a high content of the antibiotics in the blood, when these suppositories are administered by the intra-anal route. The content of antibiotics is higher than the » those levels which are achieved per se by the individual anal administration of each component.

The suppositories according to the invention are able to have a long and effective action against various diseases

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are called eu achieve. These suppositories contain a combination of macrolide antibiotics and broad spectrum antibiotics.

The invention is based on the knowledge that the combination » tion aue a macrolide antibiotic such as Spiramycin (SIM), Erythromycin (SH), Leucomycin (LH), Oleando mycin (Olli), xovobiocin (HB) or the like, these Compounds generally viewed as macrolide antibiotics, with a brittle spectrum antibiotic such as chloramphenicol (CP), tetracycline (SC) or the like, in suppository form, higher blooded each Antibiotic can achieve than this by the individual administration of each antibiotic alone the Pail 1st. This phenomenon is new and completely unexpected.

To show this new effect, suppositories are used that contain a combination of equal amounts (down to the strength) of the above-mentioned antibiotics Administered to rats, from which blood is drawn periodically to determine the antibiotic blood levels au. The results obtained are summarized in Table I below.

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dosage
Cmg / kg) - 4 - Slut content (mcg / ml) 5 hours after
the App
reaching 200
200 Table I. -1 hour after
the App
reaching 7.1
10.1 200
200 • 46.4
38.2 6.0
9.6 Active substance 200
200 40.8
41.0 3 ₉ 9
8.2 SPM + CP 200
200 'SPM ^c
CP 28.0
35.3 7.2
9.5 EM * CP 200
200 EM
CP 49.1
38.4 15.6 '
13.3 - IM + CP 200
200 SM
OP 162.0
40.5 6.8 OIH + CP 200
200 OIH
CP 51.5
3.3 8.0 RB + CP 200
200 NB
CP 56.1
4.1 4.1 SPM + TC 200
200 SPM
TC 24.4
2.8 6.9 EM + TC 200
200 TG 43.0
2.8 12.5 IM + TC 200 IH
TO . 140.5
3.5 2.6 OEM + IC 200 OIM
TC 12.4 2.6 NB ₊ IG 200 NB
TC 13.8 1.0 SPM 200 SPM 8.2 1.9 EH 200 EM 14.1 10.5 IH 200 IH 75.0 1.4 OIH 200 OLM 2.2 HB NB 0.7 CP CP TC TC

09843/1582

The suppositories containing the antibiotic combination th, result in considerably higher blood levels than the 7-match suppositories, which contain the individual antibiotics. In the suppositories according to the invention, oleum "- Cocoa is used as a carrier, with such microorganisms-Btamme are used as reading microorganisms, the opposite are sensitive to one of the antibiotics but have a sensitivity of less than 1/20 to the other antibiotic. The blood contents determined in a similar manner are given in Tables II, III below and IV combined.

It is known that the absorption of active ingredients in suppositories depends to a considerable extent on the properties of the carrier used. High blood contents are achieved by the suppositories according to the invention even when liquid carriers, such as. Sesainöl _s peanut oil or the like, in addition to solid supports, which are generally used, such as, for example be used Oleumkakao, Oleumlanolin or the like. This fact emerges from the values summarized in Table IZ.

You chemical configurations of each antibiotic practice regardless of whether these antibiotics are in the form of the free bases or the various salts, no noticeable effects. This is also possible from the Table II.

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! Bafeelle II

Active ingredient dosage combination = - carrier (mg / kg) nations " relationship

SPM + CP
SPM + GP

SPM
SPM

OP
CP

SPM citrate
+ 0P

SPM citrate

200 200

200 200

200 200

200 200

200 200

aoo

1: 1

1: 1

Blood gels, mcg / ml

1 hour close to 5 hours aacii outer meeting of the Verafcreichiaig reaching

Sesame-
oil SPM
OP 62.6
45.4 12.3
13.7 Oletua
kakap SPM
CP 44.0
40.2 5.2
11.0 Sesame-
31 SPM 8.2 2.3 Olettm
cocoa SPM 18.8 4.1 Sesame-
oil CP 3.0 2.0 Oleum
cocoa CP 2.6 1.2 Sesame-
oil SPM
CP 77.2
55.6 10.0
16.7 Oleum
cocoa SPM 8.5 2.6

909843/15 ORIGINAL INSPECTED

»C i Ö ι

The combination or mixing ratio of the two antibiotics (hereinafter referred to as A and B) is described in more detail below. If the content of the active ingredient A in the blood is to be increased, then the amount of B in the suppositories can be up to 1 weight ^, based on the weight of the active ingredient A _{9 can be} reduced "as shown in Table III" However, the addition of at least 10% by weight of the active ingredient B ₉ based on the weight of the active ingredient A _{9 is} beneficial to stabilized effects to achieve. If, on the other hand, the content of the active substance B in the blood is to be increased, then the addition of at least 1% by weight of the active substance A, based on the weight of the active substance B, is also necessary. Therefore, the combination ratio of the two active ingredients can fluctuate within extremely wide ranges, with compliance with which the gate parts according to the invention are achieved.

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Table III

Combination reserved
nlfl of the active ingredients
SPK: CP

CO
O
CD
OO

100: : O 100, 5 1 100 s 3 100 : : 10 100 s 50 100: : 100 O : 100 .1 : 100 3 : 100 10 : 100 50 : 100 100 : 100

Dosage of the active ingredients

(mg / kg)

Carrier: SesamSl

SPM + OP

200 + 0 200 + 2 200 + 6 200 + 20 200 + 100 200 + 200

SPM levels

Blood content (mog / oil) Hour after. 5 hours of administration- of administration Chung

7.4 11.9 40.5 38.2 6O ₁ S 5a »1

3.6 5.3 6.1 8 * 9

0 + 200

2 + 200

6 + 200

20 + 200

100 + 200

200 + 200

OT levels

6.8 16.1 21.5 44.0 47.7

2, .2

5.8

915191

'As mentioned above »give Suppositorienr a grain-Mnation of at least one Hakroli & antibiotic and at least one Breitbandapektrumantibiotiloim contain higher blood content @ at each antibiotic than those suppositories which the individual antibiotics alone contained" = th _s regardless of the used Srägertyp * the the antibiotic & derivative used in each case or the mixing ratio of the two antibiotics »In any case, the advantageous results according to the invention are achieved«,

The following example explains the invention without restricting it,

g spiramycin citrate, 10.0 g chloramphenicol and 50 g.

smonostsarat are put in a mortar, on what the mixture under slow Sugab® v. © n sesas oil for setting an! nd volume of 100 au. is rubbed. These Mixture is designated as suppository A ".

The suppository B is made in the same way as the suppository A, but no chloramphenicol is added. The suppository G is made in the same way manufactured like Siippositorium A, but with the Spiramycin citrate is omitted.

The suppositories A, B and C are each viscous liquids, Ba are suppositories of the so-called infusion type ο These suppositories are administered to rabbits that weigh 2.4 - 2.6 kg _f and the administration takes place via the anal route in one volume of 5 ml using a syringe. Immediately after the infusion, a sudden

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prevented on the suppository mass by means of the Eooher Sjps. 5 ral blood will be drawn from the neck artery © Ines each rabbit In each case as, © fe 0.5 _f 1 _g 2, 3 to two 5 stimuli after the administration day eatffiOiSEsem, wsasaiäf the blood samples are ssntrifuged “ad the ifetivity i @ s? . üfo © ^ =

Fluid determined after a BiossalyseiEiatho & e c The results are in the Eabsll © IF

the fabeile IT nates-? aEwendimg vem three

subtilis FOI-219 ASGC 6653 (reeistent against c & l) is used as test microörgaiiisiELUS aur BestinssEiiag myclzt, while Bssc & eriehia coli, HIH ISSS 15676 (resistant to spiramycin) zvun. 2 © is used by aol.

SPM
GP Oiabell © IV Blitteehalt® &'
_SM * _ Sti (it Hours. SPH 3B _f Q
45 ^ 2 25,
16 _p I, 14 »© CP 0.5
Hours,, 1
Bump O
5 4.8 3 _pp , 0 2.6 200
200 96 _s 0
48.8 81
52, 3 2 ₉ 2 2, , 2 1.8 200 "9.5 8 _p 6th .0 200 2.1 2,

s d £ © s @ a results is sa © rsefeea »daeg ijmt © ^ ¥ © rwendtmg r Suppoeltorien, which the discovery ate SpiraEQroin «nd l ^ ssaap & iinic ©! contain, closer blood content can be determined f ^ tesi? © application of suppositories, which are each spiral or contain GMorampheniool alone. This experig®igt clearly the surprising »experience game« »

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As above. © swSimtß know instead of Ser free Bas © derivatives of AirsäMöMlss la the inventive suppoeitorien T © rweM @ t wes? I © a. Examples of these derivatives are © SItest © _g Xastxate «-Hydrociiloride and Phosphate

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Claims (13)

Claims 1. Suppository, characterized by a mixture of a macrolide antibiotic and a broad spectrum antibiotic as well as a pharmaceutically acceptable carrier. 2. suppository according to claim 1, characterized in that that the macroidantibiotifcum from spiramycin, erythromycin, Leuoomycin, oleandomycin or novobiocin. 3. suppository according to claim 1, characterized in gekennseiohr.at, that the broad spectrum antibiotic consists of chloramphenicol or tetracycline. 4. suppository according to claim 1, characterized in that that the pharmaceutically acceptable carrier from Oleumkakac, Oleum lanolin, sesame oil, or peanut oil. 5. suppository according to claim 1, characterized® that at least one of the antibiotics in the suppository in the form of its citrus, tortrato, hydrochloride or phos » phats included 1st. 6. suppository according to claim 1 _f, characterized in that the dosage of Antiblotilnuns is approximately 200 mg per kg of body weight. 7. suppository according to claim 1, characterized in that the amount of the antibiotic is at least 1 Gev / ichts- ^, based on the amount of the second antibiotic, " 8. suppository according to claim 1, characterized in that that the amount of an antibiotic is at least 10 # based 909843/1582 BAD ORSGiNAL - • 13 to the weight of the second antibiotic «. 9. suppository according to claim 1, characterized by iohnet, that the mixing ratio of the antibiotics varies between 100: 10 and 10: 100, based on weight, 10. Suppository, characterized by a mixture of at least 1 weight-jS one of spiramycin, erythromycin, Leucomyoin, oleandomycin or novobiocin existing macroliu antibiotic and at least 1% by weight of a broad spectrum spectrum consisting of chloramphenicol or tetracycline antibiotics and a pharmaceutically acceptable carrier, 11. suppository according to claim 10, characterized in that that the dosage of the antibiotic is approximately 200 mg per kg of body weight. 12. Suppository according to claim 1O _9, characterized in that the pharmaceutically acceptable carrier consists of oleum cocoa, oleum lanolin, sesame oil or peanut oil. 13. Suppository according to claim 12, characterized in that that the mixing ratio of the antibiotics varies between 100: 10 and 10: 100 »based on weight. H. suppository according to claim 10, characterized in that the suppository at least one of the antibiotics in form of its citrate, xartrate, hydrochloride or phosphate contains. 909843/1582