RU2698820C1 - Preparation for treating mastitis in cows in lactation period - Google Patents

Abstract

FIELD: veterinary science.

SUBSTANCE: invention relates to veterinary science and represents a preparation for treating mastitis in lactation cows containing two penicillin antibiotics, one of which is a cloxacillin sodium salt, and a base, characterized in that the second antibiotic used is an amoxicillin trihydrate, the base is a Riken DMG emulsifier and distilled monoglyceride, and additionally contains an anti-inflammatory agent prednisolone in the following ratio of components, wt%: amoxicillin trihydrate – 2.5–3.5, cloxacillin sodium salt – 4.5–5.5, prednisolone – 0.28–0.32, Riken DMG emulsifier – 3.0, distilled monoglyceride – 1.0, Vaseline oil – up to 100.

EFFECT: invention allows higher clinical effectiveness in various forms of mastitis in cows during lactation.

1 cl, 5 tbl, 4 ex

Description

The invention relates to the field of veterinary medicine.

Mastitis is an inflammation of the mammary gland that occurs as a result of exposure to mechanical, thermal, chemical and biological factors.

The disease develops as a result of errors in the maintenance and operation of animals, non-compliance with the sanitary parameters of the microclimate, and violations of machine milking technology. As a result of prolonged irritation of the breast tissue, aseptic inflammation can occur, reducing the local and general resistance of the body, creating favorable conditions for the penetration and reproduction of pathogenic and conditionally pathogenic microflora, leading to the development of various forms of mastitis.

Breast diseases are widespread and cause significant economic damage to livestock. It consists of the lack of milk, premature culling of cows, high incidence of young animals, the cost of treatment. All this reduces the production and economic efficiency of dairy cattle [Vasiliev V.V. Economic damage from milk in mastitis of cows // Veterinary medicine. - No. 1. - 2008. - S. 32-34].

Currently, various drugs are available for the treatment of mastitis cows. As bactericidal agents, they may include aminoglycosides, macrolides, tetracyclines, sulfanilamides, polymyxins, fluoroquinolones, etc. But not all of them give the desired effect, which is primarily due to a decrease in the sensitivity of microflora to these substances, which causes mastitis, due to violations of the frequency of use and long time of use.

In this regard, there is a need to create new highly effective antimicrobial drugs with a wide spectrum of action, allowing to cure various forms of mastitis in the shortest possible time.

Known drug Lactobay, intended for the treatment of mastitis of bacterial etiology in cows during lactation. In one syringe dispenser as active substances it contains: ampicillin in the form of sodium salt - 75 mg and cloxacillin in the form of sodium salt - 200 mg, and as auxiliary substances liquid paraffin - 3.291 g and white soft paraffin - up to 5.0 g. In appearance, it is a homogeneous suspension of light yellow color. Lactobay is injected intracisternally into each affected quarter of the udder in a single dose of 5 g, three times with an interval of 12 hours [Instructions for use Laktobay, registration certificate number 826-3-29.13-1733 No.PVI-3-4.5 / 01827].

The disadvantage of this drug is that many microorganisms have resistance to ampicillin.

The well-known drug Mastamox is a combined anti-mastitis drug, which includes amoxicillin, cloxacillin and dexamethasone. The syringe dose (5 g) contains the active ingredients: Cloxacillin sodium salt - 200 mg, Amoxicillin trihydrate - 75 mg, Dexamethasone sodium phosphate - 1.45 mg and excipients - up to 5 g. Mastamox is administered with an interval of 12 hours. The course of treatment is 2-3 days [http://ukrzoovet.com.ua/shop/krs/veterinarnye-preparaty-534/protivomastitnye-preparaty/mastamoks-shprits-5g-detail].

The disadvantage of this drug is that by the degree of exposure to the body it belongs to hazard class 3 - substances are moderately hazardous (according to GOST 12.1.007-76).

The well-known drug Bovaclox DC for the treatment and prevention of mastitis in cows during the dry period, administered once, intracisternally in all quarters of the udder immediately after the lactation period, in a single dose of 4.5 g (1 syringe dispenser). The preparation contains the following components: ampicillin trihydrate - 250 mg, cloxacillin benzathine salt - 500 mg, aluminum stearate - 135 mg, liquid paraffin - up to 4.5 g [Instructions for use of Bovaclox DC, registration certificate number 826-3-6.13-1345№ PVI-3-5.7 / 02261].

The disadvantage of this drug is that it is used only in the dry period.

Known drug Mastiveks for the treatment of mastitis in cows, sheep and goats during lactation, containing (10 g): 250 mg of cloxacillin, 200 mg of neomycin sulfate, 500 mg of sulfadimidine, 8 mg of chymotrypsin, sodium methylparaben - 3.5 mg , sodium propylparaben - 5.3 mg, polyethylene glycol - up to 10 g. The drug is administered 3-5 times with an interval of 12 hours [Instructions for use of Mastiveks, registration certificate number 724-3-21.13-1536 No. PVI-3-4.9 / 00208 ].

The disadvantage of this drug is the time for rejection of milk, which is 96 hours and a relatively large volume (10 g) of a single dose.

Known drug Mastilayn - a combined anti-mastitis drug. The syringe dose (5 g) contains the active ingredients: Cloxacillin sodium salt - 200 mg, amoxicillin trihydrate - 75 mg; excipients: glycerin, benzyl alcohol, sodium carboxymethyl cellulose, distilled water - up to 5 g. Mastiline is administered intracisternally with an interval of 12 hours. The course of treatment is 1.5-2 days [Instructions for use of Mastiline, registration certificate number RK-VP-4-2609-14].

The disadvantage of Mastiline compared with the proposed drug is the lack of substances that provide anti-inflammatory effect and the presence of benzyl alcohol in the composition.

The prototype of the technical solution is the drug Mamifort, used to treat mastitis in cows, sheep and goats during lactation. In one syringe dispenser (8 g), the preparation contains ampicillin (sodium salt) - 75 mg and cloxacillin (sodium salt) - 200 mg as active substances; excipients: butylhydroxytoluene, white soft paraffin, liquid paraffin. Mamifort is administered intracisternally three times with an interval of 12 hours to cows in a single dose of 8 g, sheep and goats - 4 g to each quarter of the udder [Instructions for use of the drug Mamifort, registration certificate number 724-3-7.14-2216 No. PVI-3-1.4 / 01587].

The disadvantage of this drug is a decrease in its therapeutic efficacy even when a relatively large single dose (8 g) is used (compared with analog drugs, the introduction volume of which is mainly 5 g), associated with the development of resistance of microorganisms to ampicillin with prolonged use. In addition, the active substances of the drug are excreted from the mammary gland 3 days (72 hours) after the last injection, which leads to the rejection of a large amount of milk.

The technical result of the invention is to increase therapeutic efficacy and reduce the time for rejection of milk.

The technical result is achieved by the fact that in the preparation for the treatment of mastitis in cows during lactation, containing two antibiotics of the penicillin group, one of which is cloxacillin sodium salt, and the base, according to the invention, amoxicillin trihydrate is used as the second antibiotic, and Ricken emulsifier is used as the base DMG and distilled monoglyceride, and additionally contains an anti-inflammatory agent prednisolone in the following ratio of components, wt. %:

amoxicillin trihydrate - 2.5-3.5

Cloxacillin sodium salt - 4.5-5.5

prednisone - 0.28-0.32

emulsifier Ricken DMG - 3.0

distilled monoglyceride - 1.0

Vaseline oil - up to 100.

Compared with the prototype drug, the salient features of the invention are the introduction of amoxicillin into the formulation, which has a higher antimicrobial activity against a number of microorganisms than ampicillin; the combined use of amoxicillin and cloxacillin provides a synergism of antimicrobial substances and an increase in the spectrum of action of the claimed drug, which reduces the formation of resistance in microorganisms and helps to increase the effectiveness of treatment. Adding prednisone to the drug provides an anti-inflammatory effect, while amoxicillin is able to reduce the potentially negative effect of the hormone on animals, and the base helps to remove active components of the drug from the mammary gland 60 hours after the last injection.

The achievement of the technical result from the use of the proposed preparation is explained by the fact that amoxicillin, a semisynthetic penicillin antibiotic included in the preparation, has bactericidal properties, is active against most gram-positive and gram-negative bacteria isolated from the udder of cows with mastitis, including staphylococci and streptococci, including S. agalactiae, S. uberis, S. dysagalactiae, as well as Corynebacterium spp., C. pyogenes, E. coli, Bacillus cereus, Bacteroides spp., Campylobacter spp., Klebsiella spp., Pasteurella spp. [Yakovlev V.P., Yakovlev S.V. Rational antimicrobial pharmacotherapy. - M .: “Litter”, 2003. - 1004 p.].

According to the antimicrobial spectrum, amoxicillin is the most active among all oral penicillins and cephalosporins, in particular, against cocci with an intermediate level of resistance to penicillin. Somewhat stronger than ampicillin, the antibiotic acts on E. faecalis and salmonella [Kozlov S.N., Strachunsky L.S. Modern Antimicrobial Chemotherapy: A Guide for Physicians. - M .: Medical Information Agency LLC, 2009. - 448 p.].

The use of prolonged amoxicillin helps to reduce the side effects of corticosteroids [Arkhipov A.A., Stollar A.T. Adequate treatment for acute mastitis is the key to the well-being of the herd // Veterinary medicine. - No. 11. - 2008. - S. 15-17].

Cloxacillin is an antibiotic that is active against both gram-negative and gram-positive microorganisms: Staphylococcus spp., Corynebacterium diphteriae, Neisseria gonorrhoeae, Pseudomonas aeruginosa. In addition, cloxacillin is active against microorganisms that produce penicillinase, therefore it is effective in the treatment of mixed infections caused by gram-positive microorganisms [Yakovlev SV, Yakovlev VP Beta-lactam antibiotics // Consilium medicum Ukraina. - No. 1. - 2008. - S. 5-14].

The target of antibiotics in the microbial cell are the trans- and carboxypeptidase enzymes involved in the synthesis of the main component of the outer membrane of both gram-positive and gram-negative microorganisms - peptidoglycan [Sidorenko S.V. Yakovlev S.V. β-lactam antibiotics // Regular releases of breast cancer. Antibiotics. - No. 21. - 1997. - S. 2].

Prednisolone has an anti-inflammatory effect, reduces inflammation and swelling of the tissues of the udder. The anti-inflammatory effect is due to an increase in the synthesis of lipocortin, which inhibits phospholipase A ₂ , blocks the liberalization of arachidonic acid and the biosynthesis of endoperoxide, prostaglandins, leukotrienes (contributing to the development of inflammation, allergies and other pathological processes). It stabilizes lysosome membranes, inhibits the synthesis of hyaluronidase, reduces the production of lymphokines. Affects the alternative and exudative phases of inflammation, prevents the spread of the inflammatory process. The restriction of the migration of monocytes into the focus of inflammation and the inhibition of fibroblast proliferation determine the antiproliferative effect. It suppresses the formation of mucopolysaccharides and collagenase activity, increases the content of red blood cells and platelets in the blood, reduces lymphocytes, eosinophils, monocytes, basophils [Mashkovsky MD Medicines - 15th ed., Rev., Rev. and add. - M: LLC "Publishing House New Wave", 2005. - 1200 p.].

The distilled monoglyceride and emulsifier introduced into the preparation are used as emulsifiers and stabilizers of edible fats, cosmetic creams, pharmaceutical ointments, plasticizers [Chemical Encyclopedia. In 5 volumes: volume 1: A-Darzan / red.-col .: Knunyants (chap. Red.) And others. - M .: Soviet Encyclopedia, 1988. - vol. 1. - 623 p.].

Riken DMG - a product of high purity, is a highly active emulsifier. It is made of hydrogenated palm oil with a sliding melting point in the range of 63-68 ° C. Made from raw materials that have not been genetically modified. It stabilizes emulsions and provides a good and stable distribution of water in spreads, increases elasticity [E. Solovieva, V. Karagodina. Use of an emulsifier in spreads // Dairy industry. - No. 10. 2004. - S. 42-43].

Petroleum jelly is a mixture of refined hydrocarbons obtained from liquid oil. Transparent colorless oily liquid without taste and odor; practically insoluble in water and alcohol, soluble in ether, chloroform, gasoline. Miscible with all vegetable oils except castor oil. It is used in pharmacy as a basis for ointments and liniment. [Big medical encyclopedia [in 30 volumes]. / Ch. ed. Acad. B.V. Petrovsky; [Acad. honey. sciences of the USSR]. T. 3. - M .: Soviet Encyclopedia, 1976. - 584 p.: Ill.].

The claimed drug for the treatment of mastitis in cows is used during lactation for the treatment of all forms of inflammation of the mammary gland. Before the introduction of the drug, the secretions of the udder are removed from the affected lobe and disposed of, the nipple is disinfected. The contents of the syringe tube or vial are heated to 37 ° C before use, shaken thoroughly until a uniform suspension is obtained, 5 ml are taken from the vial into a sterile syringe. The syringe or syringe tube is tightly pressed to the outer opening of the nipple canal, the drug is injected into the nipple cistern by carefully pressing the syringe plunger. After the introduction, a light massage of the nipple of the affected lobe of the udder is conducted from the bottom up. Depending on the severity of the inflammatory process, the drug is administered in a dose of 5 ml twice a day with an interval of 12 hours until the affected portion of the udder is completely cured (2-4 injections).

During treatment and for 60 hours after the last administration of the drug, milk from the affected lobes of the udder is dispensed into a separate bowl, neutralized and disposed of, and the animals are fed from the remaining lobes of the udder after boiling.

The drug for the treatment of mastitis in cows during lactation is made as follows. To obtain a dispersed medium, the Rikan DMG emulsifier and distilled monoglyceride are melted in a reactor with a contact thermometer, loop heating and cooling, in a prescription amount of liquid paraffin at a temperature of 70 ° C. Then the dispersed medium is cooled to 30-35 ° C and, with stirring with a high-speed stirrer, sodium salt, amoxicillin trihydrate and prednisolone, preliminarily ground in a ball mill, are introduced sequentially with an interval of 15 minutes. After the introduction of all components, stirring is continued for another 15-20 minutes. Then the drug is fed into the hopper for packaging. The finished preparation is packaged in 5 ml in syringe dispensers equipped with a cannula for intracisternal administration and sealed with protective caps, or 100 ml in orange glass bottles, sealed with rubber stoppers and reinforced with aluminum caps.

In appearance, the drug for the treatment of mastitis in cows during lactation is a stable, oily suspension of a viscous consistency with a specific odor, white in color with a cream tint. At a temperature of 37 ° C, the suspension has a more liquid consistency. The drug completely retains its original properties (appearance, color, authenticity, mass fraction of amoxicillin, cloxacillin and prednisolone, microbial purity, mechanical inclusions) and does not delaminate for 24 months at temperatures from + 5 ° С to + 25 ° С.

The use of milk for human consumption is allowed 60 hours after the last injection of the claimed drug with the complete disappearance of the clinical signs of mastitis. Slaughter of animals for meat is allowed no earlier than 7 days after the administration of the drug. Meat of animals forced to be killed earlier than this period can be used for the production of meat and bone meal or for feed to fur animals.

The essence of the technical solution is illustrated by examples.

Example 1. To identify the optimal ratio of components and the effectiveness of the drug, three formulations were compiled:

Recipe No. 1: amoxicillin trihydrate - 2.5%, cloxacillin sodium salt - 5.5%, prednisolone - 0.3%, emulsifier Riken DMG - 3.0%, distilled monoglyceride - 1.0%, liquid paraffin - up to 100 %

Recipe No. 2: amoxicillin trihydrate - 3.0%, cloxacillin sodium salt - 5.0%, prednisolone - 0.3%, emulsifier Riken DMG - 3.0%, distilled monoglyceride - 1.0%, liquid paraffin - up to 100 %

Recipe No. 3: amoxicillin trihydrate - 3.5%, cloxacillin sodium salt - 4.5%, prednisone - 0.3%, emulsifier Riken DMG - 3.0%, distilled monoglyceride - 1.0%, liquid paraffin - up to 100 %

The study of the antimicrobial activity of the drug was carried out by the method of serial dilutions in a liquid nutrient medium. As a liquid nutrient medium, meat-peptone broth was used. When determining the sensitivity of streptococci to the medium, 1% glucose solution was added.

The main solution of the drug was prepared at the rate of 1000 μg / ml (by the sum of active substances). A working solution was prepared from the main solution of the preparation.

4.5 ml of meat-peptone broth were poured into 16 sterile tubes. 4.5 ml of the preparation was added to 1 tube, mixed, after which 4.5 ml of the resulting solution was transferred to the next tube, thus continuing dilution to 15 tubes. As a control of culture growth, a 16 test tube containing no preparation was used.

Daily agar cultures were washed with a sterile 0.9% sodium chloride solution. According to the turbidity standard, the concentration of 500 million microbial cells in 1 ml was determined. Then, by a method of successive dilutions, a concentration of 5 million microbial cells was obtained. For this purpose, the cultivation of cultures was carried out in 2 tubes with isotonic solution. In 1 test tube containing 9 ml of isotonic solution, 1 ml of culture with a concentration of 500 million microbial cells in 1 ml was added, the contents were mixed and 1 ml was transferred into a 2 test tube with 9 ml of 0.9% sodium chloride solution, the culture concentration was 5 million microbial cells. 0.5 ml of the prepared suspension were sown in all 16 tubes. In working tubes, the concentration of culture was 250 thousand microbial cells.

Crops were incubated at 37 ° C for 18-20 hours. After the incubation period, the result was taken into account. The minimum bacteriostatic concentration (MBsK) was considered the lowest concentration that causes a visible growth retardation of the culture (clear broth).

To establish the bactericidal effect of the drug from test tubes with a transparent medium, after careful agitation, cultures were carried out on solid nutrient media. The minimum bactericidal concentration (MBcc) was considered the lowest concentration at which complete inhibition of culture growth was noted when reseeding on meat-peptone agar that did not contain the drug.

To identify the optimal ratio of the components in the preparation, the antimicrobial activity of different formulations was compared with the activity of the starting active ingredients - amoxicillin and cloxacillin. The results of a study of the antimicrobial activity of amoxicillin, cloxacillin and their various combinations are presented in table 1.

Studies have shown that both components of the drug have high antimicrobial activity against E. coli 866 and Staph. aureus 209P (table 1).

When studying the bacteriostatic and bactericidal activity of cloxacillin, it was found that it has a high activity against Staph. aureus 209P 1.95 and 3.9 μg / ml, and for E. coli 866 - 3.9 and 7.8 μg / ml, respectively. The bacteriostatic and bactericidal activity of amoxicillin in relation to E. coli 866 was 1.95 and 3.9 μg / ml, and for Staph. aureus 209P - 0.12 and 0.23 μg / ml, respectively.

With respect to E. coli, MBSK formulations No. 2 and No. 3 compared to MBsK in Cloxacillin decreased 4 times, and in No. 1 - 2 times. Compared with the activity of amoxicillin MBsK, formulations No. 2 and No. 3 decreased by 2 times, while in No. 1 it did not change.

In relation to Staph. aureus 209Р MBsK of formulation No. 1 and No. 3 compared to MBXK of cloxacillin decreased by 8.5 times, and in No. 2 - by 16.3 times. MBsK of the formulation No. 1 and No. 3 in comparison with the activity of amoxicillin increased by 2 times, and No. 2 did not change.

The minimum bactericidal concentration of all the studied formulations exceeded the bacteriostatic 2 times.

Based on the data obtained, it was found that the most pronounced antimicrobial effect has the formulation No. 2. The combined use of amoxicillin and cloxacillin allowed to reduce the minimum bacteriostatic concentration in relation to the studied cultures, which indicates the synergistic effect of the constituent components. In this regard, the antimicrobial activity of the second formulation was studied in more detail.

When conducting bacteriological studies, microorganisms isolated from the secret of mastitis patients with cows, as well as museum strains were used as test cultures. The results of the experiments are presented in table 2.

As follows from the data presented (table 2), the drug has a wide spectrum and high antimicrobial effect against potential causative agents of mastitis. Its minimum inhibitory concentration for staphylococci was 0.098-0.39 μg / ml, for streptococci and enterococci - 0.19-1.56 μg / ml, and Escherichia - 0.19-0.78 μg / ml.

Thus, the claimed drug has a high antimicrobial activity against potential causative agents of mastitis in cattle.

Example 2. Scientific and production experience was carried out on the basis of ZAO Slavyanskoe of the Verkhovsky district of the Oryol region on 27 cows selected on the basis of analogues.

The diagnosis of subclinical mastitis was made comprehensively, taking into account the anamnesis, clinical examination and the results of milk tests. The reaction with the diagnostic reagent was carried out using a milk control plate MKP-2. For this purpose, 1 ml of milk was dispensed from each lobe of the mammary gland into the corresponding wells, then 2 ml of the Kenotest diagnostic reagent was added using a dispenser, and stirred by rotating the plate in a horizontal plane for 10-15 seconds. Accounting for the reaction was carried out for 10-15 seconds. by the formation of a jelly-like clot or discoloration of the mixture.

Animals of the control group (n = 13) were used Mamifort according to the instructions for its use. Sick animals of the experimental group (n = 14) after milking in the affected lobe of the udder, the claimed preparation was administered intracisternally at a dose of 5.0 ml 2-3 times with an interval of 12 hours, in the following ratio of components, wt. %:

amoxicillin trihydrate - 3.0

cloxacillin sodium salt - 5.0

prednisone - 0.3

emulsifier Ricken DMG - 3.0

distilled monoglyceride - 1.0

Vaseline oil - up to 100.

As follows from the data presented in table 3, the therapeutic efficacy of the claimed drug was 100% with subclinical mastitis, while in the control group the treatment efficiency was lower by 7.7% and amounted to 92.3%.

Example 3. Scientific and production experience was conducted on the basis of LLC “SP Vyaznovatovka” Nizhnedevitsky district of the Voronezh region on 28 cows, selected on the basis of analogues. Animals were kept under the same conditions of feeding and keeping.

The diagnosis of catarrhal mastitis was made taking into account the history, clinical examination and analysis of milk. Animals of the control group (n = 14) were used Mamifort according to the instructions for use. After milking the cows of the experimental group (n = 14), after milking, the claimed preparation was administered intracisternally in the dose of 5.0 ml 3-4 times with an interval of 12 hours, with the following ratio of components, wt. %:

amoxicillin trihydrate - 3.0

cloxacillin sodium salt - 5.0

prednisone - 0.3

emulsifier Ricken DMG - 3.0

distilled monoglyceride - 1.0

Vaseline oil - up to 100.

As follows from the data presented in table 4, the therapeutic efficacy of the claimed drug was 92.9% with catarrhal mastitis, in the control group, the treatment efficiency was lower than the claimed drug by 7.2% and amounted to 85.7%.

Example 4. Scientific and production experience was carried out on the basis of LLC "Agrotech-Garant" Verkhne-Toidensky "Anninsky district of the Voronezh region on 18 cows, selected on the basis of analogues. Animals were kept in the same conditions.

The diagnosis of purulent-catarrhal mastitis was made taking into account the history, clinical examination and analysis of milk. Animals of the control group (n = 10) were used Mamifort according to the instructions for use. Sick cows of the experimental group (n = 8) after milking in the affected lobes of the udder were intracisternally injected with the claimed preparation in a dose of 5.0 ml 3-4 times with an interval of 12 hours, in the following ratio of components, wt. %:

amoxicillin trihydrate - 3.0

cloxacillin sodium salt - 5.0

prednisone - 0.3

emulsifier Ricken DMG - 3.0

distilled monoglyceride - 1.0

Vaseline oil - up to 100.

As follows from the data presented in table 5, the therapeutic efficacy of the claimed drug was 87.5% with purulent-catarrhal mastitis, in the control group the treatment efficiency was lower than in the experimental group by 17.5% and amounted to 70.0%.

The claimed drug for the treatment of mastitis in cows during lactation is superior to the imported comparison drug Mamifort with therapeutic efficacy due to the use of cloxacillin sodium salt and amoxicillin trihydrate, which expands the spectrum of antibacterial action, and prednisolone, which has an anti-inflammatory effect that reduces inflammation and swelling of the udder tissue, in the form of stable oil-based suspensions. The drug does not have an irritating effect and can be widely used in production conditions of livestock farms for the treatment of subclinical, catarrhal and purulent-catarrhal mastitis.

Claims (2)

A drug for treating mastitis in cows during lactation, containing two antibiotics of the penicillin group, one of which is cloxacillin sodium salt, and a base, characterized in that amoxicillin trihydrate is used as the second antibiotic, emulsifier Riken DMG and distilled monoglyceride are used, and additionally contains an anti-inflammatory agent prednisone in the following ratio of components, wt. %: amoxicillin trihydrate 2.5-3.5 cloxacillin sodium salt 4,5-5,5 prednisone 0.28-0.32 emulsifier Ricken DMG 3.0 distilled monoglyceride 1,0 liquid paraffin up to 100