Methylthioninium Chloride Enteric-coated Sustained-Release Tablets

Table of contents

1 Basic Information 1

2 Domestic Listing Status 2

2.1 Domestic Registration Status of Original Drug 2

2.2 Generic Drug Approval 3

2.3 Consistency Evaluation Application and Approval Status 3

2.4 Generic Drug Application Status 3

2.5 Clinical Filing Status 3

3 Reference Preparation 3

4 Reference Preparation Patent Information 3

5 Market Situation 3

5.1 Medical Insurance Information 3

5.2 Centralized Procurement Information 3

5.3 Sales Status 3

5.4 Bidding Information 4

6 Active Pharmaceutical Ingredient (API) Research 4

6.1 API Pharmacopoeia Information 4

6.2 API Filing Information 4

7 Formulation Research 4

7.1 Target Product Quality Overview 4

7.2 Formulation Pharmacopoeia Information 5

1 Basic Information

Methylene Blue (Methylthionine Chloride) is a water-soluble thiazine dye that promotes the non-enzymatic redox conversion of methemoglobin (MetHb) to hemoglobin. In situ, methylene blue is first converted by NADPH reductase to colorless leucomethylene blue (LMB). The LMB molecule then reduces the ferric iron in MetHb to the ferrous state of normal hemoglobin. Therefore, methylene blue can act as an antidote for the acute symptomatic treatment of methemoglobinemia caused by various chemicals.

Additionally, methylene blue is known as a "vital dye," meaning a dye or stain that can penetrate live cells or tissues without causing immediate, noticeable degenerative changes. Methylene blue passes through cell membranes into the cytoplasm of actively absorbing cells, such as those in the small intestine and colon, thereby staining the epithelium of these organs. Vital dyes like methylene blue enhance the surface structure of lesions through active mucosal staining absorption to highlight contrast and thereby emphasize differences between cell types. This property of methylene blue is used clinically for diagnosing lesions in organs like the gastrointestinal tract.

On May 6, 2011, the methylene blue injection developed by Provepharm SAS was approved for market by the EMA as an antidote under the brand name Methylthioninium Chloride Proveblue, with a specification of 5 mg/ml (2 ml, 10 ml). On April 8, 2016, the same company's methylene blue injection received FDA approval under the brand name Proveblue, with the same specification. On August 19, 2020, the delayed-release methylene blue tablet developed by Cosmo S.p.A. was approved by the EMA as a diagnostic agent under the brand name Lumeblue, with a specification of 25 mg, and on June 11, 2024, it was approved for import to China by the NMPA.

The essential information for Lumeblue, an original product marketed in the EU, is shown in Table 1-1.

Table 1-1 Basic Information

Item	Methylene Blue Enteric-Coated Sustained-Release Tablets
English name	Methylthioninium Chloride Enteric-coated Sustained-Release Tablets
Structural Formula
Molecular Formula	C₁₆H₁₈ClN₃S·xH₂O
Molecular Weight	319.86（anhydrous）
Dosage Form	Tablet (enteric-coated, sustained-release)
Specification	25 mg
Appearance	Grayish-white to light blue, round, biconvex, enteric-coated tablets, approximately 9.5 mm x 5.3 mm in size.
Formulation Image
Formulation	Active Ingredient：Methylthioninium chloride 25 mg. Tablet Core Excipients：Soy lecithin 3 mg, stearic acid 50, microcrystalline cellulose, hydroxypropyl methylcellulose 2208, mannitol, talc, colloidal silicon dioxide anhydrous, magnesium stearate. Coating：Methacrylic acid-methyl methacrylate copolymer (1:1), methacrylic acid-methyl methacrylate copolymer (1:2), talc, titani
BCS	/
Registration Category	Class 4
ATC	V Miscellaneous > V04 Diagnostic agents > V04C Other diagnostic agents > V04CX Other diagnostic agents
Indication	A diagnostic agent to enhance the visualization of colorectal lesions in adults undergoing screening or surveillance colonoscopy.
Dosing Protocol	Dosage and Administration for Adults, including the Elderly (≥65 years) The recommended total dose is 200 mg, equivalent to eight 25 mg tablets. This dose must be taken orally during or after the administration of a low-volume (e.g., 2 liters) or high-volume (e.g., 4 liters) polyethylene glycol (PEG) bowel cleansing agent and completed on the evening before the colonoscopy. This ensures that the tablets have enough time to reach the colon and locally release methylthioninium chloride prior to the procedure. Special Populations - Elderly: No dosage adjustment is necessary for elderly patients (≥65 years). - Renal Impairment: No adjustment is needed for patients with mild renal impairment. Caution is advised for moderate to severe renal impairment, as data are limited, and methylthioninium chloride is primarily excreted by the kidneys. - Hepatic Impairment: No adjustment is required for patients with mild to moderate hepatic impairment. There is no experience with use in patients with severe hepatic impairment. - Pediatric: The safety and efficacy of this drug in children under 18 years have not been established. Method of Administration Oral. Tablets should be swallowed whole and must not be crushed, split, or chewed. Patients should follow the dosing regimen as part of the PEG bowel cleansing protocol: l Take the first dose of 3 tablets after drinking at least 1 L of bowel cleanser; l Take the second dose of 3 tablets 1 hour after the first dose; l Take the final dose of 2 tablets 1 hour after the second dose.
Storage	Store at room temperature
Packaging	Blister packs
Shelf Life	3 years

2 Domestic Market Approval Status

2.1 Original Drug Domestic Registration Status

The original formulation has been imported into China, as detailed in Table 2-1.

Table 2-1 Import Approval

Approval Number	Drug Name	Specification	Marketing Authorization Holder	Manufacturer	Initial Approval Date
NMPA HJ20240037	Methylene Blue Enteric-Coated Sustained-Release Tablets	25 mg (as C₁₆H₁₈ClN₃S)	Bridging Pharma Limited	Cosmo S.p.A.	2024-06-11

2.2 Generic Drug Approval

As of September 25, no company has obtained production approval for a generic version of this product.

2.3 Consistency Evaluation Application and Approval Status

As of September 25, no company has obtained production approval for a generic version of this product.

2.4 Generic Drug Application Status

As of September 25, no company has submitted a marketing application for a generic version of this product.

2.5 Clinical Record Filing Status

As of September 25, no company has filed a bioequivalence (BE) study record for this product.

3. Reference Listed Drug

Table 3-1 National Administration’s Published Reference Drug Information

Serial Number	Generic Name	Brand Name	Specification	Authorization Holder	Note 1	Note 2
60-39	Methylthioninium Chloride Enteric-coated Sustained-Release Tablets	Lumeblue	25mg	Alfasigma S.p.A.	——	Marketed in the EU

4. Reference Drug Patent Information

This product has been on the market for many years, and there are no patents within the protection period for the reference drug. Therefore, there is no infringement risk for the generic version of this product.

Application Number / Date	Patent Title	Patent Holder	Legal Status	Technology Type
201180012333.0（2011.03.021）	Solid composition for oral administration of dyes and its diagnostic use	Cosmo Technologies Ltd.	Authorized, valid until March 20, 2031	Formulation

5. Market Situation

5.1 Insurance Information

This product is not covered under the national medical insurance program.

5.2 Centralized Procurement Information**

As of September 25, this product has not been included in the national centralized procurement catalog.

5.3 Sales Information

This product was approved for import on June 11, 2024. No sales data has been publicly disclosed.

5.4 Tender Information

This product was approved for import on June 11, 2024. No tender data has been publicly disclosed.

6. Active Pharmaceutical Ingredient (API) Research

6.1 API Pharmacopoeia Information

According to our search, quality standards for this API are listed in the ChP, EP, BP, and USP.

6.2 API Filing Information

As of September 25, there are only three filing numbers for Methylene Blue, with one in status A.

7. Formulation Research

7.1 Target Product Quality Profile

Table 7-1 Target Product Quality Profile (QTPP)

Product Attribute	Target	Rationale
Dosage Form	Tablet	Same dosage form
Packing	25 mg	Same packing
Route of administration	Oral	Same route of administration
Composition	Active ingredient：25 mg Methylene Blue Core Excipients: 3 mg Soy Lecithin, Stearic Acid 50, Microcrystalline Cellulose, Hypromellose 2208, Mannitol, Talc, Colloidal Anhydrous Silica, Magnesium Stearate Coating: Methacrylic Acid-Methyl Methacrylate Copolymer (1:1), Methacrylic Acid-Methyl Methacrylate Copolymer (1:2), Talc, Titanium Dioxide, Triethyl Citrate	The types of excipients are the same as the RLD.
Drug Quality Attributes	Appearance	Pharmaceutical equivalence requirements
	Identification
	Dissolution
	Related Substances
	Assay
	Microbial Limits
Storage	Room temperature storage	Same as RLD
Packaging	Aluminum-plastic blister	Same as RLD
Shelf Life	3 years	Equal to or better than RLD

7.2 Formulation Pharmacopoeia Information

A search revealed that no pharmacopoeia information is currently available for this formulation.

Methylthioninium Chloride Enteric-coated Sustained-Release Tablets

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