| HS Code | 496239 |
| Product | Aprotinin(Trypsinum Inhibere) Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions |
| Cas Number | 9087-70-1 |
| Chemical Name | Bovine basic pancreatic trypsin inhibitor (BPTI) |
| Molecular Formula | C284H432N84O79S7 |
| Molecular Weight | Approximately 6511 Da |
| Appearance | White or almost white powder |
| Solubility | Freely soluble in water and isotonic sodium chloride solution; practically insoluble in organic solvents |
| Storage Conditions | Store at 2 to 8°C, protected from light and moisture |
| Shelf Life | 24 months when stored under recommended conditions |
| Dosage Forms | Tablets, injections, capsules, powders, granules, premix and solutions |
| Therapeutic Category | Antifibrinolytic serine protease inhibitor |
| Mechanism Of Action | Inhibits trypsin, plasmin and kallikrein, thereby reducing fibrinolysis and excessive blood loss |
| Veterinary Indications | Adjunctive therapy for pancreatitis, hyperfibrinolytic hemorrhage and conditions involving excessive protease activity |
| Quality Standard | Veterinary grade API conforming to pharmacopoeial requirements for animal use |
As an accredited Aprotinin(Trypsinum Inhibere) Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Aprotinin (Trypsinum Inhibere) veterinary grade API packaged in sealed drums, 25 kg per drum, for tablets, injections, capsules, powders, granules, premix, solutions. |
| Container Loading (20′ FCL) | Loaded in 20′ FCL: palletized drums/cartons, secured with straps and dunnage, ensuring safe transport of Aprotinin veterinary grade API. |
| Shipping | Shipments of Aprotinin (Trypsinum Inhibere) Veterinary Grade API are temperature-controlled and protected from light and moisture. Product is packed in sealed, inert containers with desiccants to ensure stability. International transport follows IATA/IMDG regulations, with full documentation including MSDS and COA. Expedited cold-chain delivery available upon request. |
| Storage | Store in a cool, dry, well-ventilated area at 2–8°C, protected from light and moisture. Keep in tightly sealed original container, away from incompatible substances. Avoid freezing and excessive heat. Use within stated expiry period once opened. Ensure work area is clean to prevent contamination. |
| Shelf Life | Shelf Life: 24 months from manufacture when stored sealed, dry, protected from light, at controlled room temperature. |
Aseptic processing lines built for small-volume parenteral veterinary products receive aprotinin sourced against Ph. Eur. 0579 and current EU GMP Part II with an endotoxin specification not exceeding 0.5 EU/mg when the labelled dose exceeds 10 mL per animal. In equine and canine surgical services where intraoperative fibrinolysis is documented on thromboelastography, the finished injection is normalised to 10,000 KIU/mL; the gravimetric addition is not fixed because lot-to-lot specific activity and loss on drying shift the mass basis, so each batch is corrected after compendial assay. Dissolution is carried out in water for injection at 2–8 °C, adjusted to pH 4.5–5.5 with dilute hydrochloric acid or sodium hydroxide, and filtered through a 0.22 µm polyethersulfone membrane prior to aseptic filling into Type I borosilicate glass vials. Nitrogen overlay during filling reduces oxidative denaturation, and the line operates with fill-volume tolerance of ±0.05 mL for 10 mL vials using peristaltic pump heads fitted with single-use tubing. Terminal steam sterilisation is avoided because activity loss above 90 °C exceeds the pharmacopoeial limit; this is the primary process conflict in injectable manufacturing. For hospitals requiring longer shelf-life, the same filtered solution is lyophilised in vials under a controlled lyophilisation cycle with primary drying at −30 °C and secondary drying below +25 °C. Finished product types include 10 mL and 20 mL single-dose vials for intravenous infusion, lyophilised powder in 10 mL vials for reconstitution to 10,000 KIU/mL, and 50 mL infusion bags diluted in normal saline. The solution must be stored at 2–8 °C and protected from light; freeze-thaw cycles are not permitted because subvisible peptide aggregates form after the third cycle. Incompatibilities include strong oxidising agents and silicone oil from over-lubricated filling needles, which can accelerate aggregation and reduce filterability.
Aprotinin is incorporated into serum-free viral vaccine culture media because trypsin-like proteases released from lysed cells degrade viral envelope proteins during harvest and downstream purification. In this application the material is not a finished drug product but a raw material in cell culture media, and compendial quality is assessed against Ph. Eur. 0579, with ancillary material risk management conducted under USP <1043> and viral safety documentation aligned to ICH Q5A(R2). The working concentration in medium is 5–50 µg/mL, with lower concentrations used for continuous cell lines and higher concentrations required in high-cell-density perfusion bioreactors where proteolytic load rises with viable cell density. Addition ratio is expressed as mass per litre of complete medium, not per animal dose. The downstream production process involves reconstitution of lyophilised aprotinin in cell-culture-grade water, sterile filtration through a 0.1 µm filter, and aseptic addition to the basal medium after pH and osmolality adjustment. Single-use mixing bags or stainless-steel preparation vessels are used; in perfusion systems, the inhibitor is metered continuously into the bioreactor feed line. The terminal product forms are ready-to-use complete media, concentrated nutrient feeds, and process intermediates used in the manufacture of veterinary vaccines such as canine parvovirus and feline calicivirus antigens. Repeated freeze-thaw of stock solutions must not exceed 2 cycles; otherwise activity loss and aggregate formation may occur. Supplier qualification audits in this segment require endotoxin certificates, residual solvent data under VICH GL18, and virus inactivation documentation for the raw material supply chain.
Compounding pharmacies and veterinary ophthalmology services that manage melting corneal ulcers in horses prepare aprotinin ophthalmic solutions at 0.5% w/v to 1.0% w/v, with osmolality adjusted to 280–320 mOsm/kg using sodium chloride or mannitol after addition of the API. The compliance framework for sterile ophthalmic preparations references Ph. Eur. 5.1.1 for sterility, Ph. Eur. 5.1.3 for preservative efficacy when multi-dose containers are used, and USP <797> for extemporaneous compounding in the United States. The formulation addition ratio is not fixed by mass per volume because activity varies by lot; instead, the batch certificate specific activity is used to calculate the weight needed to achieve 10,000 KIU/mL or the equivalent percentage. Downstream production uses an ISO class 5 laminar airflow workbench, a 0.22 µm membrane filter, and low-density polyethylene dropper bottles; the solution is filtered after pH adjustment because aprotinin becomes less stable at pH above 7.5. Terminal product types include 5 mL and 10 mL ophthalmic dropper bottles, unit-dose irrigation syringes for intraoperative corneal lavage, and ocular surface biomatrix rinses. Beyond-use dating is commonly limited to 14 days at 2–8 °C because of peptide instability in aqueous solution. Multi-dose containers containing benzalkonium chloride should be subjected to compatibility screening, because preservative-associated corneal epithelial toxicity can confound clinical assessment of epithelial healing.
For oral delivery beyond the gastric pylorus, aprotinin is granulated with microcrystalline cellulose and povidone in a fluid-bed processor and coated with an enteric polymer to prevent pepsin-mediated inactivation. The API content in the core granule is 2–8% w/w before coating, with the enteric coat applied to 10–15% weight gain using a pH-sensitive methacrylic acid copolymer dispersion. Compliance for oral veterinary dosage forms requires Ph. Eur. 5.1.4 microbiological quality, Ph. Eur. 2.9.3 or USP <711> dissolution testing for delayed-release articles, and residual solvent limits under VICH GL18. The downstream production process uses a top-spray fluid-bed granulator with inlet air temperature not exceeding 40 °C during drying, because higher temperatures reduce trypsin-inhibitory activity. After coating, granules are screened through a 1.0 mm sieve and filled into hard gelatin capsules or sachets. Terminal finished product types are enteric-coated capsules, delayed-release granules in unit-dose sachets, and direct-compression tablets where the coating is applied after tablet compression. Published data for this specific veterinary oral configuration is limited; therefore the formulation ratio and coating thickness should be verified by in vitro dissolution at pH 1.2 followed by pH 6.8 and by target-species pharmacokinetic studies before registration. Gastric acid exposure above 30 minutes in the dissolution test indicates incomplete enteric protection and requires coat weight adjustment.
Hospital pharmacies that manage chronic granulation tissue in equine distal limb wounds prepare aprotinin irrigation solutions at 0.05–0.2% w/v in Ringer’s lactate or sterile normal saline. Protease burden in wound exudate, particularly neutrophil elastase and plasmin, degrades fibronectin and delays closure; the inhibitor is used as an adjunct to surgical debridement. Compliance is set by Ph. Eur. 5.1.1 when the product is labelled sterile, Ph. Eur. 5.1.4 for non-sterile lavage if the wound is classified as contaminated, and USP <797> for compounded sterile preparations. The addition ratio is activity-normalised to 5,000–10,000 KIU per 100 mL of irrigation fluid; hypertonic solutions above 320 mOsm/kg are avoided because granulation tissue is sensitive to osmotic stress. Downstream production occurs in closed-system transfer devices and polyvinyl chloride-free bags; the solution is filtered through 0.45 µm membranes for particulate control and used within 24 hours after reconstitution. Terminal product forms include 50 mL and 100 mL wound lavage bottles, 10 mL unit-dose irrigation syringes, and freeze-dried powder for dilution at the point of care. The powder is filled into vials under nitrogen and stored at 2–8 °C before reconstitution. Alcohol-based irrigation solutions are not suitable primary diluents because alcohol denatures the peptide and reduces anti-protease activity.
In neonatal calf research protocols where aprotinin is added to colostrum or milk replacer to protect orally administered immunoglobulins from tryptic digestion, the premix is prepared as a concentrated powder blend and diluted to a target of 10,000–50,000 KIU/kg of liquid feed. This is not an authorised zootechnical additive in the European Union under Regulation (EC) No 1831/2003, and commercial feed incorporation is therefore not permitted unless a specific authorisation exists in the destination market. Compliance for such research-use premixes follows Ph. Eur. 5.1.4 for microbiological quality and VICH GL18 for residual solvents; analytical verification uses Ph. Eur. 0579 for trypsin-inhibitory activity. The production process includes geometric dilution of the API with lactose monohydrate or maltodextrin, dry blending in a V-type mixer, and filling into foil-lined multiwall paper bags. Terminal product types are research-use premix powders, water-soluble granules for liquid feed preparation, and lyophilised powders for oral drench solutions. The product must be added to milk replacer at or below 40 °C to preserve activity. Published data for this specific configuration is limited to experimental protocols and should not be extrapolated to commercial farm use without regulatory review.
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Designated Trypsinum Inhibere in compendial nomenclature, Aprotinin Veterinary Grade API is a basic polypeptide of bovine lung origin with a molecular mass of approximately 6512 Da and the CAS registry number 9087-70-1. The material is supplied as a lyophilized powder or cake and is standardized as a starting material for tablets, injections, capsules, powders, granules, premix, and solutions. Inhibition of serine proteases is stoichiometric and reversible; one aprotinin molecule binds one trypsin, plasmin, plasma kallikrein, or tissue kallikrein molecule. Manufacturer-assigned model codes, APR-VET-LYO for the lyophilized injectable-grade powder and APR-VET-OG for the oral granulation-grade powder, distinguish endotoxin limits, particulate control, and residual moisture specifications rather than the active polypeptide itself.
Compendial grade material is evaluated against the European Pharmacopoeia monograph for Aprotinin, Ph. Eur. 0579. Specific activity is the principal release parameter and is expressed in Ph. Eur. units; the monograph sets the limit as not less than 3.0 Ph. Eur. U/mg on the dried basis. The assay measures inhibition of kallikrein or trypsin under defined pH and temperature conditions. Identification is confirmed by comparing the retention time with an aprotinin reference standard using liquid chromatography according to Ph. Eur. 2.2.29. Peptide mapping by mass spectrometry under Ph. Eur. 2.2.43 is used to confirm the primary structure and to detect oxidized or deamidated variants. Related proteins and higher-molecular-mass aggregates are controlled by validated size-exclusion or reversed-phase methods. Bacterial endotoxin limits are mandatory for injectable-grade material and are determined by Ph. Eur. 2.6.14. Loss on drying is determined by Ph. Eur. 2.5.12, and residual solvents by Ph. Eur. 2.4.24.
| Parameter | Value / limit | Reference method |
|---|---|---|
| Specific activity | ≥3.0 Ph. Eur. U/mg on dried basis | Ph. Eur. 0579 assay |
| Molecular mass | 6512 Da | MALDI-TOF MS, Ph. Eur. 2.2.43 |
| Appearance | White to almost white lyophilized powder or cake | Visual inspection |
| Bacterial endotoxins | Injectable grade: stated on label, normally ≤0.5 IU/mg | Ph. Eur. 2.6.14 |
| Water content | Lyophilized powder: ≤5.0% w/w unless otherwise justified | Ph. Eur. 2.5.12 |
| Residual solvents | Complies with veterinary risk assessment; no chlorinated solvents used | Ph. Eur. 2.4.24 |
Manufacture of the API is expected to follow ICH Q7 Good Manufacturing Practice for active pharmaceutical ingredients. Analytical procedure validation follows ICH Q2(R1); stability evaluation follows ICH Q1A(R2) or the corresponding VICH guidance. The certificate of analysis should state the specific activity, endotoxin load, and water content of each batch because oral and injectable grades are supplied under separate specifications.
Batch release for veterinary dosage-form manufacturing uses the same specific activity method as human grade, but the oral grade may allow a wider endotoxin acceptance criterion when the target species and route of administration do not require parenteral limits. The oral granulation-grade powder still requires control of bacterial count, moulds, and yeasts according to Ph. Eur. 5.1.4 or the relevant veterinary monograph. Bioburden reduction is achieved by validated dry heat or gamma irradiation cycles only if stability data show no loss of specific activity. End-product testing follows the relevant monograph for the finished veterinary medicinal product, not the API monograph alone.
Process stability is evaluated with forced degradation studies at acidic, neutral, and alkaline pH, oxidative stress, and elevated temperature. In those studies, the principal degradation products are deamidated forms, disulfide-scrambled aggregates, and lower-molecular-mass fragments. High-performance size-exclusion chromatography with UV detection at 214 nm is used to resolve aggregates from the monomer peak. Reversed-phase liquid chromatography under Ph. Eur. 2.2.29 resolves oxidation products. The sum of related substances must be within the acceptance criterion stated in the marketing authorization dossier.
For injectable solution manufacturing, the lyophilized powder is reconstituted in Water for Injections at 2–8 °C. Complete dissolution is achieved under low-shear stirring; the resulting solution is clear to slightly opalescent. The pH of the formulation is adjusted to 4.0–5.0 using dilute hydrochloric acid or an acetate buffer system; this range reduces disulfide exchange and aggregation during holding. Sterile filtration through a 0.22 µm polyethersulfone or polyvinylidene fluoride membrane is preferred over terminal steam sterilization unless container-closure and stability data demonstrate potency retention across the sterilization cycle. Low-protein-binding membranes are specified because polypeptide adsorption to nylon or regenerated cellulose can reduce assay recovery by more than 10% in dilute solutions. Hold times between dissolution and filtration are validated by assay and purity testing; storage of the bulk solution at room temperature for extended periods is not recommended unless supported by bracketed stability data.
Production-scale failure modes include foaming during reconstitution, which denatures the polypeptide at the air-liquid interface, and incomplete dissolution if the powder is added too rapidly. Controlled addition into the vortex of the stirred water followed by a rest period minimizes these effects. Filter capacity should be confirmed by differential pressure monitoring; a rapid pressure rise across the membrane indicates aggregate formation or filter blocking. In automated filling lines, the filling needle should be flushed with Water for Injections at regular intervals to prevent protein deposition at the needle tip. The injection solution should not be mixed with strongly alkaline buffers or organic solvents; precipitation and activity loss occur under those conditions. Type I glass vials with siliconized chlorobutyl stoppers are common; silicone oil levels should be controlled because excessive silicone can adsorb polypeptide. For veterinary injectables where cost constraints apply, multilayer plastic bags are used only if sorption studies demonstrate recovery not less than 95% after 24 h storage.
The polypeptide is susceptible to peptic hydrolysis in gastric fluid; therefore, tablets, capsules, and granules intended for trypsin inhibition in the small intestine require an enteric coating or matrix system. A methacrylic acid-ethyl acrylate copolymer dispersion is applied with plasticizer and cured under conditions that do not cause pellet agglomeration. Dissolution is evaluated according to Ph. Eur. 2.9.3 using a two-stage method: 0.1 mol/L hydrochloric acid for 2 h, followed by phosphate buffer at pH 6.8. The acceptance criterion for delayed-release veterinary products is commonly not less than 75% release within 45 min in the buffer stage, or as justified by the target species and route of administration. For capsules, the enteric coating can be applied to the capsule shell or to granules filled into hard capsules; the latter requires a film-forming coating with sufficient mechanical flexibility to withstand capsule filling.
Granulation of aprotinin-containing powders is performed by low-shear wet granulation or dry granulation. High-shear granulation can induce local heating and peptide aggregation; published data for this specific peptide in high-shear wet granulation are limited, and process validation is required before scale-up. Roller compaction and dry sieving are therefore preferred for powders and granules. The binder system is selected from non-reducing polymers such as povidone or hypromellose; reducing sugars are avoided because Maillard-type degradation of the polypeptide can reduce specific activity. Moisture content of the dried granules is controlled to not more than 5.0% w/w for hard capsules and 3.0% w/w for moisture-sensitive formulations. Hard capsule formulations require the API to be compacted or triturated with a diluent to prevent segregation. Powder flow is characterized by angle of repose and Carr index according to Ph. Eur. 2.9.36; a Carr index above 25% indicates the need for granulation before capsule filling.
Feed premixes and oral powders require a different particle-size and uniformity profile than injection-grade material. The oral granulation-grade powder is geometrically diluted with lactose monohydrate or dextrose-free maize starch in steps not exceeding 1:10 mass ratio per dilution stage until the target concentration is reached. Blend uniformity is verified by multiple sampling points according to Ph. Eur. 2.9.40 or an equivalent veterinary feed method. The powder should be stored in sealed aluminium-laminated pouches with desiccant; relative humidity above 60% increases water uptake and can reduce flowability. Premix concentrations are expressed in Ph. Eur. units per kg of feed; the conversion between units and mass is based on the measured specific activity of each batch. Sampling points for blend validation include the top, middle, and bottom of the blender, with an acceptance criterion of RSD ≤5.0% for the active assay. If the blend is to be pelleted, the pellet mill conditioning temperature and moisture should be confirmed because steam conditioning can introduce heat and water into the blend. Published data for aprotinin stability during feed pelleting are limited; therefore, pilot-scale recovery studies are required before commercial manufacture.
For solutions prepared for drinking water, aprotinin is dissolved in a stock solution at acidic pH and then diluted; calcium-containing hard water can cause turbidity due to phosphate or carbonate interactions. Published data for this specific veterinary solution configuration are limited; therefore, compatibility with local water quality should be confirmed by robustness testing. For powders and granules intended for direct administration, the particle-size distribution is controlled by sieving through 500 µm and 150 µm screens, with the target range selected by the downstream dosage form. A free-flowing granule is obtained by roller compaction and dry sieving rather than by wet mass extrusion, because the high water activity during extrusion can promote aggregate formation. In automated sachet filling lines, granules with high electrostatic charge may adhere to contact surfaces; static elimination and controlled room humidity below 55% are used to maintain fill weight uniformity.
The differentiating properties of aprotinin are defined by its Kunitz-type structure and its reversible stoichiometric binding to multiple serine proteases. Plant-derived soybean trypsin inhibitor also belongs to the Kunitz family but has a higher molecular mass and narrower practical spectrum in veterinary formulations. Synthetic low-molecular-mass inhibitors such as gabexate mesylate are not polypeptides and are eliminated by esterase hydrolysis; they do not provide the same broad kallikrein-plasmin-trypsin binding profile. Alpha-1 antitrypsin is a serpin that inhibits elastase and trypsin by irreversible covalent trapping, whereas aprotinin forms a reversible complex that can dissociate under certain conditions. This mechanistic difference affects formulation and assay design: aprotinin activity is measured by residual protease inhibition, not by esterase substrates.
| Inhibitor | Source/type | Molecular mass | Inhibition mode | Main formulation consequence |
|---|---|---|---|---|
| Aprotinin | Bovine lung polypeptide | 6512 Da | Reversible stoichiometric | Acidic pH processing preferred |
| Soybean trypsin inhibitor | Plant Kunitz-type protein | ~20 100 Da | Reversible stoichiometric | Higher viscosity in solution |
| Alpha-1 antitrypsin | Human plasma serpin | ~52 000 Da | Irreversible covalent | Cold-chain handling; serpin polymerization risk |
| Gabexate mesylate | Synthetic small molecule | <500 Da | Active-site esterase inhibitor | Solution pH and ester stability control |
Operational boundaries are defined by the sensitivity of the polypeptide to alkaline pH, oxidizing agents, and reducing sugars. The API should not be compounded with strong oxidizers or exposed to direct sunlight for prolonged periods. Reconstituted solutions should be stored at 2–8 °C and used within the validated hold time; repeated freeze-thaw cycles are not recommended because they can generate aggregates. The API is not intended for use in formulations containing strong reducing agents or aldehyde-based crosslinkers. For parenteral formulations, compatibility with preservatives must be tested; no general limit is assigned across all veterinary species. Where tablet or premix manufacturing requires dry heat or irradiation, the effect on specific activity must be demonstrated by assay and peptide mapping because polypeptide APIs may undergo radiolytic or thermal fragmentation. Published data for species-specific parenteral compatibility are limited; veterinary formulators must conduct target animal safety studies under the relevant regulatory framework.
