Proteolytic enzymes

Proteolytic Enzymes (Proteases) as Dietary Supplements

1. Identity: Names, Sources, and Forms

Definition and Nomenclature

Proteolytic enzymes, also called proteases, are enzymes that break down protein; they are made by animals, plants, fungi, and bacteria. They are essential for many important processes in the body and are also called peptidases, proteases, or proteinases. As a class, they catalyze the hydrolysis of peptide bonds in proteins, cleaving them into smaller peptides or free amino acids. When used as dietary supplements, they may function either locally in the digestive tract or — depending on the form and delivery mechanism — systemically, after intestinal absorption.

Key Individual Enzymes Found in Supplements

Some proteolytic enzymes that may be found in supplements include bromelain, chymotrypsin, ficin, papain, serrapeptase, and trypsin. Each has a distinct natural source and biochemical identity:

• Bromelain — a complex natural mixture of protein-digesting enzymes derived from the fruit or stem of pineapple (Ananas comosus), used as a phytomedical compound with a range of therapeutic benefits. EC 3.4.22.33 (Fruit Bromelain) and EC 3.4.22.32 (Stem Bromelain) are both types of bromelain that belong to the peptidase family C1. The stem is the most common commercial source. The major compounds in bromelain include endopeptidases, phosphatases, glucosidases, peroxidases, cellulases, and various glycoproteins.
• Papain — a cysteine protease (EC 3.4.22.2) derived from Carica papaya. Papain is obtained from the milky juice (latex) of unripe papayas, by drying and pulverizing the latex. The papaya fruit, and particularly its sap, contains a mixture of proteolytic enzymes such as papain and chymopapain.
• Serratiopeptidase (Serrapeptase) — serratiopeptidase (also known as serralysin, serrapeptase, serratiapeptase, or serratia peptidase) is a proteolytic enzyme produced by enterobacterium Serratia sp. E-15, now known as Serratia marcescens ATCC 21074, a microorganism originally isolated in the late 1960s from silkworm (Bombyx mori L.) intestine, where it is present and allows the emerging moth to dissolve its cocoon. It is a metalloprotease with a molecular weight of 45–60 kDa that contains zinc.
• Trypsin and Chymotrypsin — trypsin and chymotrypsin derived from pigs and cows are some of the most common animal-based proteolytic enzymes added to supplement blends.
• Pancreatin (Pancrelipase) — a mixture of enzymes (lipase, amylase, and protease) obtained from the pancreas of pigs; these enzymes enhance digestion of fats, proteins, and starches in the upper duodenum and jejunum.
• Ficin — a proteolytic enzyme derived from fig (Ficus) latex, sometimes included in multi-enzyme supplement blends.

Dosage Forms and Preparations

Proteolytic enzyme supplements are available in capsules, gel caps, chewables, powders, and tablets. Some supplements contain a single type of proteolytic enzyme, while others contain a combination. Bromelain, papain, pancreatin, trypsin, and chymotrypsin are proteolytic enzymes that are commonly added to proteolytic supplement blends.

A critical formulation consideration for systemic use is protection from gastric acid. Being sensitive to gastric degradation, serratiopeptidase is conventionally given orally in the form of enteric-coated tablet formulations. Pancreatic enzyme preparations exist as both coated and uncoated tablets; uncoated tablets are not as bioavailable because degradation may occur in the acid of the stomach.

Notable commercial multi-enzyme formulations include Wobenzym and Phlogenzym, which are among the most extensively studied in clinical trials. Three commonly investigated complexes are: (i) Phlogenzym, which contains the proteolytic enzymes bromelain (90 mg/tab), trypsin, and rutin; (ii) Wobenzym, which contains bromelain (45 mg/tab), papain, trypsin, chymotrypsin, pancreatin, lipase, and amylase; and (iii) Wobenzym N, which contains bromelain (45 mg/tab), trypsin, papain, chymotrypsin, pancreatin, and rutin.

2. Traditional and Historical Use

Bromelain and Pineapple

The history of bromelain dates back to the ancient civilizations of South America, where the pineapple plant (Ananas comosus) is native. Indigenous peoples in Central and South America, particularly in regions like the Amazon rainforest and the Caribbean, used various parts of the pineapple plant for medicinal purposes, including treating digestive issues, reducing inflammation, and healing wounds. Pineapple has been used as part of traditional folk medicine since ancient times and continues to be present in various herbal preparations.

The first isolation of bromelain was recorded by the Venezuelan chemist Vicente Marcano in 1891 by fermenting the fruit of the pineapple. In 1892, Russell Henry Chittenden, assisted by Elliott P. Joslin and Frank Sherman Meara, investigated the matter more completely and called it "bromelin." Originally, bromelain was exclusively derived from Hawaiian pineapple stems, but it is now also manufactured in Taiwan, Thailand, Brazil, and Puerto Rico.

Papain and Papaya

Traditional medicine systems across Asia, Africa, South America, and the Pacific employ papaya for digestive disorders, infections, inflammation, wound healing, metabolic disorders, and reproductive health. Historically, Carica papaya has been used in traditional medicine systems across various cultures for its therapeutic properties. In folk medicine, the use of papaya was not only limited to treating digestive issues but also extended to treating ulcers; the unripe fruit, seeds, and leaves were commonly used in poultices and herbal concoctions to treat external and internal ulcers.

The first written reports on possible healing effects go back to the Spaniard Oviedo (1526). In Ayurveda, leaves and latex are used as digestive stimulants, anthelmintics, and wound-healing agents. African communities employ papaya for malaria, jaundice, and inflammatory conditions, while Southeast Asian practices use leaf juice to manage dengue and elevate platelet counts. Carica papaya is traditionally used to treat various skin disorders, including wounds, and is widely used in developing countries as an effective and readily available treatment for various wounds, particularly burns.

Serratiopeptidase

Serrapeptase has no "traditional" use in the same sense as botanical or herbal agents. Its origin from silkworm gut led to early experimental use in Japan and Europe for locally reducing inflammation and mucus; it was adopted clinically in the 1960s–1970s in some regions for inflammatory conditions and post-operative swelling. First approved for therapeutic use in Japan in 1968, serratiopeptidase has been employed as a dietary supplement and pharmaceutical agent primarily for its anti-inflammatory, analgesic, anti-edemic, and mucolytic properties.

Modern Systematization in Europe

Proteolytic enzyme treatments were first popularized in Germany in the 1960s for inflammation, osteoarthritis, autoimmune diseases, and viral infections. The development of enteric-coated oral preparations during this era enabled the systemic use of proteolytic enzymes and laid the groundwork for subsequent clinical research, particularly with the Wobenzym and Phlogenzym product lines.

3. Key Constituents and Mechanisms of Action

Proteolytic (Protein-Hydrolyzing) Activity

Proteolytic enzymes break down proteins in the body or on the skin; this may help with digestion or with the breakdown of proteins involved in swelling and pain. When taken systemically, they are believed to act on protein substrates in the bloodstream and interstitial spaces, including inflammatory mediators, fibrin deposits, and immune complexes.

Anti-Inflammatory Mechanisms

Proteolytic enzymes do not suppress the inflammatory response but rather support and accelerate the controlled physiological progression of the immune response and inflammatory process. Several specific mechanisms have been proposed and investigated:

• Cytokine and immune complex modulation: Preclinical studies indicate that proteolytic enzymes have immunomodulatory and tumoricidal properties; such effects are thought to result from degradation of abnormal immune complexes. In clinical studies, oral administration of proteolytic enzymes to healthy volunteers resulted in immunomodulatory effects.
• Bradykinin, histamine, and serotonin degradation: The enzyme's mechanism involves modulating inflammatory cytokines, dissolving non-living tissue, and disrupting bacterial biofilms through interference with adhesion molecules, helping to break down proteins, reduce swelling, and alleviate pain by hydrolyzing bradykinin, histamine, and serotonin.
• Fibrinolytic and anti-edemic effects: Bromelain is widely administered for its well-recognized properties, including anti-inflammatory, antithrombotic, and fibrinolytic effects, anticancer activity, and immunomodulatory effects, in addition to being a wound-healing and circulatory-improvement agent. Serratiopeptidase is mucolytic, fibrinolytic, anti-biofilm, anti-inflammatory, and promotes wound healing.
• Platelet aggregation inhibition: Bromelain has diverse biological properties including platelet aggregation inhibition and anti-inflammatory effects, which seem to be related to proteolytic activity.
• Mucolytic activity: Serratiopeptidase has shown significant anti-inflammatory, anti-edemic, and analgesic effects in various areas including surgery, orthopaedics, otorhinolaryngology, gynaecology, and dentistry.

Biochemical Classification

Proteolytic enzymes are classified by their catalytic mechanism. Bromelain and papain are cysteine proteases, relying on a cysteine residue at the active site; they belong to the peptidase C1 (papain) family. Trypsin and chymotrypsin are serine proteases, using a serine residue as the nucleophile. Serratiopeptidase is a zinc-dependent metalloprotease of the serralysin/peptidase M10 family. These mechanistic differences mean that each enzyme has distinct substrate specificities, pH optima, and ranges of activity.

Bioavailability and Systemic Absorption

Orally, the enzymes and proteins of bromelain are absorbed intact to some degree and may possibly be helpful for digestive complaints, infections, and even metabolic problems. Enteric coating is key to systemic delivery of acid-labile enzymes: serrapeptase is reported to undergo acid hydrolysis at gastric pH, thereby decreasing stability in the gastrointestinal tract. Serrapeptase is given at a dose of 5–10 mg three times a day in enteric-coated form to maximize systemic bioavailability.

4. Scientific Evidence by Area of Use

4.1 Osteoarthritis

Numerous clinical trials have examined oral enzyme combinations as a potential new approach in managing pain in patients with osteoarthritis; oral enzyme combinations containing bromelain in combination with trypsin, both proteolytic enzymes, as well as the plant flavonoid rutin, may be an effective alternative to typical NSAIDs.

A narrative review aimed to summarize and discuss the evidence on the efficacy of oral enzyme combinations compared to the gold standard (NSAID) in the management of osteoarthritis symptoms. Nine randomized controlled trials identified in this review assessed the efficacy and safety of the oral enzyme combination containing bromelain, trypsin, and rutin in patients with osteoarthritis. Most of the studies assessed the impact of the oral enzyme combination on the improvement of the Lequesne Algofunctional index score, treatment-related pain intensity alterations, and adverse events compared to patients receiving NSAIDs.

A 2022 review looked at nine clinical studies in which people with osteoarthritis took an oral enzyme combination containing bromelain, trypsin, and an antioxidant known as rutin. The authors found the enzyme combination was as effective as NSAIDs for reducing joint pain and stiffness, with fewer side effects. A 2015 study evaluated the impact of proteolytic enzymes in comparison with the medication diclofenac in adults with moderate to severe knee osteoarthritis; the improvement in pain scores was the same in both groups and greater than the placebo, and the side effects were similar in the enzyme and placebo groups.

Several comparative studies conducted with Phlogenzym, an oral enzyme-rutin combination containing bromelain 90 mg, trypsin 48 mg, and rutin 100 mg, have demonstrated the product to be effective and safe in the treatment of osteoarthritis as compared to NSAIDs. The Phlogenzym and Wobenzym formulations have been the subject of the largest and most rigorous trials in this area. Proteolytic enzymes may be useful in reducing pain associated with moderate-to-severe knee osteoarthritis.

Evidence assessment: Evidence for the bromelain-trypsin-rutin combination in osteoarthritis is moderately strong, based on multiple randomized controlled trials with active comparators (NSAIDs), though many trials are sponsored by manufacturers and some have methodological limitations. The finding of comparable efficacy to diclofenac is notable but requires confirmation in larger, independently funded trials.

4.2 Post-Surgical and Traumatic Inflammation and Edema

Clinical trials demonstrate the effectiveness and safety of the bromelain, trypsin, and rutoside fixed-dose combination in treating edema and inflammation and facilitating the healing of wounds. The post-dental surgery setting has been one of the best-studied applications. A systematic review and meta-analysis published in PMC examined bromelain specifically after third-molar surgery. Bromelain, a pineapple-derived enzyme mixture, is a widely used agent to improve tissue regeneration; clinical and experimental data indicate a better outcome of soft tissue healing under the influence of bromelain, with proteolytic, antibacterial, anti-inflammatory, and anti-edematogenic effects accounting for this improvement at the systemic level.

Beyond digestive support, proteolytic enzymes have been explored for various therapeutic applications, including relief from chronic musculoskeletal pain, osteoarthritis, and post-surgical recovery. Systemic therapy with proteolytic enzymes before and after exhaustive exercise increased maximal concentric strength and had favorable effects on inflammatory, metabolic, and immune biomarkers.

Evidence assessment: Post-surgical swelling and edema represent one of the more robustly supported indications, particularly for bromelain and serrapeptase. However, results have varied widely, with many studies lacking robust design or placebo controls.

4.3 Temporomandibular Joint (TMJ) Osteoarthritis and Dental Applications

A systematic review assessed the effectiveness, acceptability, and safety of systemic enzyme therapy, consisting of trypsin, bromelain, and rutoside trihydrate, as an anti-inflammatory agent, either when utilized independently or in conjunction with NSAIDs. Two studies met the inclusion criteria and were assessed in the review; the bias risk was evaluated using the risk-of-bias tool for randomized trials (RoB 2), and both studies revealed highly significant results. Individuals receiving oral enzymes and diclofenac sodium combination therapy showed a significant improvement in pain reduction, better eating, and mouth opening, as well as a decrease in joint noise and jerky mandibular motions.

Serratiopeptidase is prescribed in various specialties like surgery, orthopaedics, otorhinolaryngology, gynaecology, and dentistry. In the dental context, controlled trials have examined its effect on post-antrotomy buccal swelling, with double-blind placebo-controlled designs documenting reductions in post-operative swelling.

Evidence assessment: Preliminary to moderate. The body of evidence in dental and oral surgery applications is more extensive for serratiopeptidase than for other enzymes, but overall trial quality is variable and sample sizes are generally small.

4.4 Serratiopeptidase: Anti-Inflammatory, Analgesic, and Mucolytic Evidence

A PubMed search for "Serratiopeptidase" or "Serrapeptase" revealed 74 results, showing 16 clinical trials, of which 9 were RCTs related to efficacy of serratiopeptidase. Various published studies have reflected the use of serratiopeptidase for its anti-inflammatory, anti-edemic, and analgesic effects; there were 6 clinical studies supporting these anti-inflammatory effects.

A published systematic review (Bhagat et al., 2013) concluded that: the evidence supporting the use of serratiopeptidase as an anti-inflammatory and analgesic agent is based on clinical studies of poor methodology. Only a few RCTs, which are usually placebo-controlled with small sample sizes, are available. The dose and duration of treatment were not specified in some studies, and the outcome of the study was not clearly defined in a few.

The evidence supporting the use of serratiopeptidase as an anti-inflammatory and analgesic agent is based on clinical studies of poor methodology. Only a few RCTs with small sample sizes exist. The dose and duration of treatment were not specified in some studies, and the outcome was not clearly defined in a few. Data on the safety and tolerability of serratiopeptidase is lacking in these studies.

Serratiopeptidase's applications are attributable to its versatile properties including anti-inflammatory, anti-biofilm, analgesic, anti-edemic, and fibrinolytic effects. However, the significant impact of serratiopeptidase reported needs to be backed by more scientific data.

Evidence assessment: Weak to preliminary for serratiopeptidase overall. While individual trials show positive findings in inflammation, swelling, and mucus-related conditions, the body of evidence is limited by small sample sizes, poor methodological quality, and a lack of dose-standardization across studies.

4.5 Pulmonary Fibrosis (Pilot Evidence)

In a randomized controlled trial, eligible patients were randomly assigned in a 1:1 ratio, with the supplement group receiving Serracor-NK and Serra Rx260 three times a day and the placebo group receiving placebo capsules with the same dosing schedule for a period of six months, to be taken on an empty stomach. The supplements Serracor-NK and Serra Rx260 were well tolerated without apparent interactions with the standard-of-care drugs pirfenidone or nintedanib. Liver function tests and vitals were not adversely affected by the treatment intervention and were within normal ranges throughout for all participants, indicating the supplements' safety profile.

Evidence assessment: Very preliminary. A small pilot RCT showing safety and tolerability; insufficient to draw efficacy conclusions. Larger trials are required.

4.6 Digestive Support

As a therapeutic supplement, proteolytic enzymes are primarily used to aid digestion, particularly for individuals experiencing protein digestion difficulties due to pancreatic insufficiency or other gastrointestinal disorders. Bromelain has been used to treat symptoms of indigestion, nausea, and abdominal pain. Pancreatic enzyme replacement therapy (PERT) using prescription pancrelipase is an established, FDA-approved treatment for exocrine pancreatic insufficiency (EPI); pancrelipase is a combination of lipase, protease, and amylase enzymes used to treat exocrine pancreatic insufficiency due to cystic fibrosis and other gastrointestinal disorders.

Evidence assessment: Strong for prescription pancrelipase in documented EPI; moderate to preliminary for over-the-counter plant-derived enzyme supplements (bromelain, papain) in functional digestive complaints, with less rigorous trial data available than for pharmaceutical-grade preparations.

4.7 Wound Healing and Topical Applications

Applied topically, proteolytic enzymes may help in wound debridement and burn management. Historically, papain was valued in traditional medicine as a natural remedy for treating wounds, reducing tissue swelling, and managing skin diseases; its use dates back centuries, with indigenous cultures harnessing the enzyme's properties to support wound healing and relieve pain.

Papain was used to prevent burn infections, for the defibrination of wounds, to treat insect bites, for the treatment of edema and inflammatory processes, and to accelerate wound healing. The proteolytic activity of papain facilitates the removal of necrotic tissue (debridement) in chronic or burn wounds, a mechanism that has biological plausibility and is supported by both traditional use and preclinical data.

Evidence assessment: Preliminary to moderate for topical enzymatic debridement using papain. Randomized clinical trials specifically evaluating topical bromelain for burn debridement (e.g., NexoBrid, a pharmaceutical concentrate of bromelain) have been conducted with positive results, but the over-the-counter supplement context differs from pharmaceutical-grade topical preparations.

4.8 Cancer and Oncology-Adjacent Uses

Laboratory studies suggest that proteolytic enzymes can affect the growth of cancer cells. Although proteolytic enzymes were previously reported to benefit patients with cancer, more recent studies do not support such claims. Proteolytic enzymes have not been shown to prevent or treat cancer.

Bromelain in combination with either 5-FU or cisplatin may enhance the efficacy of the chemotherapeutic drug in in vitro settings. Current evidence indicates that bromelain may have the potential to be developed into an effective anticancer agent for malignant peritoneal mesothelioma, but this evidence remains at the preclinical stage.

Evidence assessment: Laboratory and animal data are promising for certain cancer applications, but clinical evidence is insufficient and conflicting. No established clinical use for cancer treatment or prevention.

4.9 Rheumatoid Arthritis and Autoimmune Conditions

Bromelain has been used to treat medical conditions including osteoarthritis, rheumatoid arthritis, prostatitis, inflammatory bowel disease, and multiple sclerosis. Proteolytic enzymes and antioxidant combinations have been used empirically for many of these conditions. There is a growing body of evidence indicating beneficial effects exerted by the individual ingredients and their combinations on the pathophysiology of arthritis. The analgesic, anti-inflammatory, anti-edematous, anti-thrombotic, and antioxidant properties of these substances have been demonstrated in multiple in vitro and animal models.

For autoimmune diseases, evidence is lacking to support current claims.

Evidence assessment: Preliminary. Animal and in vitro data support biological plausibility; adequate human RCT evidence in rheumatoid arthritis and autoimmune diseases is lacking.

5. Body Systems and Health Areas Associated with Proteolytic Enzymes

• Digestive System: Protein digestion support, dyspepsia, functional indigestion, exocrine pancreatic insufficiency (prescription PERT)
• Musculoskeletal System: Osteoarthritis, rheumatoid arthritis, sports injuries, post-operative and post-traumatic swelling, muscle recovery
• Cardiovascular and Hematological System: Fibrinolysis, platelet aggregation modulation, thrombosis-related conditions (primarily preclinical evidence for dietary supplement forms)
• Respiratory System: Mucolytic applications in chronic airway disease, sinusitis, exploratory use in pulmonary fibrosis (pilot data only)
• Immune System: Immune complex modulation, immunomodulatory effects in healthy volunteers
• Integumentary System (Skin): Wound debridement, burn management, skin ulcers (primarily topical applications)
• Otorhinolaryngology: Post-antrotomy buccal swelling, sinusitis, secretory otitis media
• Dentistry and Oral Surgery: Post-extraction and post-impaction swelling, TMJ osteoarthritis, periodontal applications

6. Dosage Forms and Reported Dosages

Dosages vary considerably across individual enzymes, formulations, and indications. The following dosages are drawn directly from published clinical literature and product information cited in this article:

• Phlogenzym (bromelain-trypsin-rutin combination): Each tablet contains bromelain (90 mg), trypsin (48 mg), and rutin (100 mg).
• Wobenzym: Each tablet contains bromelain (45 mg), papain (60 mg), trypsin (24 mg), chymotrypsin (1 mg), pancreatin (100 mg), lipase (100 mg), amylase (100 mg), and rutin (50 mg).
• Wobenzym N formulation: The formulation contains per tablet: pancreatin 100 mg, trypsin 24 mg, and chymotrypsin 1 mg (from pancreas); bromelain 45 mg; papain 60 mg; and rutin 50 mg.
• Bromelain (as Bromelin standalone tablets): Bromelin contains bromelain 200 mg per tablet.
• Bromelain — daily dose range: Bromelain is considered to be nontoxic and may be used at daily doses of 200 to 2,000 mg per kilogram for prolonged periods of time. (Note: this figure refers to experimental dose range; typical human supplement doses are substantially lower.)
• Serratiopeptidase: Serrapeptase is given at a dose of 5–10 mg three times a day in enteric-coated form for clinical use. Commercial enteric-coated supplements commonly supply 20,000–120,000 SPU (serrapeptase units) per day.
• Pancrelipase: Each milligram contains 24 units lipase, 100 units amylase, and 100 units of protease activity. Prescription dosing for EPI is individualized based on lipase unit requirements.

Bromelain activity is also commonly expressed in gelatin-digesting units (GDU) or milk-clotting units (MCU) rather than mass, and products vary in activity per unit mass, making direct comparisons across products complex.

7. Safety Considerations and Drug Interactions

General Safety

When taken by mouth, proteolytic enzymes are possibly safe when taken appropriately. Side effects are usually mild or moderate and include stomach and intestinal complaints. In studies, proteolytic enzymes are believed to be quite safe, although they occasionally cause digestive upset and allergic reactions.

Anticoagulant Interactions

The most clinically significant interaction is with anticoagulants, particularly warfarin; papain and bromelain may potentiate the effects of blood thinners, increasing bleeding risk. The proteolytic enzyme papain might increase the blood-thinning effects of warfarin and possibly other anticoagulants; bromelain might also cause problems if combined with drugs that thin the blood, like heparin.

Antibiotic Interactions

Proteolytic enzymes may increase absorption of certain antibiotics (amoxicillin, tetracycline) and sedatives (benzodiazepines). Bromelain should not be mixed with sedative drugs and should be avoided by individuals taking antibiotics because it may increase blood concentrations of certain antibiotics.

Folate and Pancreatin

One proteolytic enzyme, pancreatin, may interfere with the absorption of vitamin B folate, so it is advisable to take a folate supplement when taking pancreatin.

Allergic Reactions

People who are allergic to kiwi and figs may be allergic to papain; when applying papain topically or ingesting it, people with these allergies should exercise caution. Bromelain carries a pineapple/latex allergy consideration; serrapeptase has rare reports of serious skin and allergic reactions.

Pre-Surgical Use

Patients scheduled for surgery should discontinue papain at least 2 weeks prior. The same general precaution applies to bromelain and other proteolytic enzymes with known antiplatelet and anticoagulant effects.

Special Populations

Pregnant and breastfeeding patients are advised to avoid papain supplements due to insufficient safety data. Pregnant or breastfeeding individuals should avoid both bromelain and serrapeptase unless cleared by a healthcare provider.

Biofilm and Anti-Infective Considerations

Through the use of enzyme inhibitors specific for cysteine proteases, it was found that the antibacterial activity of papain and bromelain is not related to their proteolytic activity but may be related to other activities, such as amidase and esterase. This finding suggests that the full pharmacological profile of these enzymes extends beyond simple proteolysis and remains an area of ongoing investigation.

Regulatory Status

In the United States, plant-derived proteolytic enzyme preparations such as bromelain and papain are sold as dietary supplements under the Dietary Supplement Health and Education Act (DSHEA) and are not FDA-approved drugs. Bromelain-containing dietary supplements are marketed with no confirmed efficacy, safety, recommended dosage, long-term safety, or adverse interaction with other medications established by regulatory authorities. Prescription pancrelipase preparations (Creon, Zenpep, Pancreaze) are FDA-approved drugs indicated for EPI and are subject to full regulatory oversight. Serratiopeptidase is used as a prescription pharmaceutical in Japan, India, and several European countries, but is sold as a dietary supplement in the United States.

References

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• Efficacy of Proteolytic Enzyme Bromelain on Health Outcomes after Third Molar Surgery: Systematic Review and Meta-Analysis — PMC (2019)
• Anti-inflammatory Role of Trypsin, Rutoside, and Bromelain Combination in Temporomandibular Joint Osteoarthritis: A Systematic Review — PMC (2024)
• Combination of Enzymes and Rutin to Manage Osteoarthritis Symptoms: Lessons from a Narrative Review of the Literature — PMC (2022)
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• Multi-Center Study Evaluating the Efficacy of Wobenzym N in Treating Knee Osteoarthritis — ClinicalTrials.gov