Enteric coating

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An enteric coating is a barrier applied to oral medication that controls the location in the digestive system where it is absorbed.

Drugs such as aspirin, which have an irritant effect on the stomach, can be coated with a substance that will only dissolve in the small intestine.

Enteric coating can also be used to prevent the acidic environment of the stomach from destroying some medications.

Enteric refers to the small intestine, therefore enteric coatings prevent release of medication before it reaches the small intestine.

Most enteric coatings work by presenting a surface that is stable at acidic pH, but breaks down rapidly at higher pH.

Cellulose Acetate Phthalate is used as an enteric coating on capsules or tablets so they don't dissolve until they reach the small intestine. Enteric coatings are selectively insoluble substances - they won't dissolve in the acidic juices of the stomach, but they will dissolve in the higher pH (above pH 5.5) of the small intestine. Serrapeptase™ Rx capsules are enteric coated because the effectiveness of the drug will be reduced by stomach acids or enzymes if left unprotected. Cellulose Acetate Phthalate 1. Nonproprietary Names • BP: Cellacefate • JP: Cellulose acetate phthalate • PhEur: Cellulosi acetas phthalas • USPNF: Cellacefate 2. Synonyms • Acetyl phthalyl cellulose; Aquacoat cPD; CAP; cellacephate; cellulose acetate benzene-1,2-dicarboxylate; cellulose acetate hydrogen 1,2-benzenedicarboxylate; cellulose acetate hydrogen phthalate; cellulose acetate monophthalate; cellulose acetophthalate; cellulose acetylphthalate. 3. Chemical Name and CAS Registry Number • Cellulose, acetate, 1,2-benzenedicarboxylate [9004-38-0] 4. Empirical Formula and Molecular Weight • Cellulose acetate phthalate is a cellulose in which about half the hydroxyl groups are acetylated, and about a quarter are esterified with one of two acid groups being phthalic acid, where the remaining acid group is free. See Section 5. 5. Structural Formula The PhEur 2002 (Suppl. 4.3) and USPNF 21 describe cellulose acetate phthalate as a reaction product of phthalic anhydride and a partial acetate ester of cellulose containing 21.5-26.0% of acetyl (C 2 H 3 O) groups, and 30.0-36.0% of phthalyl( o -carboxybenzoyl, C 8 H 5 O 3 ) groups.

6. Functional Category • Coating agent. 7. Applications in Pharmaceutical Formulation or Technology • Cellulose acetate phthalate (CAP) is used as an enteric film coating material, or as a matrix binder for tablets and capsules. 1 - 8 Such coatings resist prolonged contact with the strongly acidic gastric fluid, but dissolve in the mildly acidic or neutral intestinal environment. • Cellulose acetate phthalate is commonly applied to solid-dosage forms either by coating from organic or aqueous solvent systems or by direct compression. Concentrations generally used are 0.5-9.0% of the core weight. The addition of plasticizers improves the water resistance of this coating material, and formulations using such plasticizers are more effective than when cellulose acetate phthalate is used alone. • Cellulose acetate phthalate is compatible with many plasticizers, including acetylated monoglyceride; butyl phthalybutyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalylethyl glycolate; glycerin; propylene glycol; triacetin; triacetin citrate; and tripropionin. It is also used in combination with other coating agents such as ethyl cellulose, in drug controlled-release preparations. • Therapeutically, cellulose acetate phthalate has recently been reported to exhibit experimental microbicidal activity against sexually transmitted disease pathogens, such as the HIV-1 retrovirus. 9, 10 8. Description • Cellulose acetate phthalate is a hygroscopic, white to off-white, free-flowing powder, granule, or flake. It is tasteless and odorless, or might have a slight odor of acetic acid. 9. Pharmacopeial Specifications • See Table I. 10. Typical Properties • Density (bulk): 0.260 g/cm 3 • Density (tapped): 0.266 g/cm 3 • Melting point: 192°C. Glass transition temperature is 160-170°C. 11 • Moisture content: 2.2%. Cellulose acetate phthalate is hygroscopic and precautions are necessary to avoid excessive absorption of moisture. 12 See also Figure 1. • Solubility: practically insoluble in water, alcohols, and chlorinated and non-chlorinated hydrocarbons. Soluble in a number of ketones, esters, ether alcohols, cyclic ethers and in certain solvent mixtures. It can be soluble in certain buffered aqueous solutions as low as pH 6.0. Cellulose acetate phthalate has a solubility of =10% w/w in a wide range of solvents and solvent mixtures; Table II and Table III. • Viscosity (dynamic): a 15% w/w solution in acetone with a moisture content of 0.4% has a viscosity of 50-90 mPa s. This is a good coating solution with a honey-like consistency, but the viscosity is influenced by the purity of the solvent. 11. Stability and Storage Conditions • Slow hydrolysis of cellulose acetate phthalate will occur under prolonged adverse conditions such as high temperatures and high humidity, with a resultant increase in free acid content, viscosity, and odor of acetic acid. However, cellulose acetate phthalate is stable if stored in a well-closed container in a cool, dry place. 12. Incompatibilities • Cellulose acetate phthalate is incompatible with ferrous sulfate, ferric chloride, silver nitrate, sodium citrate, aluminum sulfate, calcium chloride, mercuric chloride, barium nitrate, basic lead acetate, and strong oxidizing agents such as strong alkalis and acids. 13. Method of Manufacture • Cellulose acetate phthalate is produced by reacting the partial acetate ester of cellulose with phthalic anhydride in the presence of a tertiary organic base such as pyridine, or a strong acid such as sulfuric acid. 14. Safety • Cellulose acetate phthalate is widely used in oral pharmaceutical products and is generally regarded as a nontoxic material, free of adverse effects. • Results of long-term feeding in rats and dogs have indicated a low oral toxicity. Rats survived daily feedings of up to 30% in the diet for up to 1 year without showing a depression in growth. Dogs fed 16 g daily in the diet for 1 year remained normal. 15. Handling Precautions • Observe normal precautions appropriate to the circumstances and quantity of material handled. Cellulose acetate phthalate may be irritant to the eyes, mucous membranes, and upper respiratory tract. Eye protection and gloves are recommended. Cellulose acetate phthalate should be handled in a well-ventilated environment; use of a respirator is recommended when handling large quantities. 16. Regulatory Status • Included in the FDA Inactive Ingredients Guide (oral tablets). Included in non-parenteral medicines licensed in the UK . 17. Related Substances • Cellulose acetate; hypromellose phthalate; polyvinyl acetate phthalate. 18. Comments • Any plasticizers that are used with cellulose acetate phthalate to improve performance should be chosen on the basis of experimental evidence. The same plasticizer used in a different tablet base coating may not yield a satisfactory product. • In using mixed solvents, it is important to dissolve the cellulose acetate phthalate in the solvent with the greater dissolving power, and then to add the second solvent. Cellulose acetate phthalate should always be added to the solvent, not the reverse. • Cellulose acetate phthalate films are permeable to certain ionic substances, such as potassium iodide and ammonium chloride. In such cases, an appropriate sealer sub-coat should be used. • A reconstituted colloidal dispersion of latex particles rather than solvent solution coating material of cellulose acetate phthalate is also available. This white, water-insoluble powder is composed of solid or semisolid sub-micrometer-sized polymer spheres with an average particle size of 0.2 µm. A typical coating system made from this latex powder is a 10-30% solid-content aqueous dispersion with a viscosity in the 50-100 mPa s range. 19. Specific References 1. Spitael J , Kinget R , Naessens K . Dissolution rate of cellulose acetate phthalate and Brönsted catalysis law. Pharm Ind 1980; 42 : 846-849. 2. Takenaka H , Kawashima Y , Lin SY . Preparation of enteric-coated microcapsules for tableting by spray-drying technique and in vitro simulation of drug release from the tablet in GI tract. J Pharm Sci 1980; 69 : 1388-1392. ( PubMed ) 3. Takenaka H , Kawashima Y , Lin SY . Polymorphism of spray-dried microencapsulated sulfamethoxazole with cellulose acetate phthalate and colloidal silica, montmorillonite, or talc. J Pharm Sci 1981; 70 : 1256-1260. ( PubMed ) 4. Stricker H , Kulke H . Rate of disintegration and passage of enteric-coated tablets in gastrointestinal tract [in German]. Pharm Ind 1981; 43 : 1018-1021. 5. Maharaj I , Nairn JG , Campbell JB . Simple rapid method for the preparation of enteric-coated microspheres. J Pharm Sci 1984; 73 : 39-42. ( PubMed ) 6. Beyger JW , Nairn JG . Some factors affecting the microencapsulation of pharmaceuticals with cellulose acetate phthalate. J Pharm Sci 1986; 75 : 573-578. ( PubMed ) 7. Lin SY , Kawashima Y . Drug release from tablets containing cellulose acetate phthalate as an additive or enteric-coating material. Pharm Res 1987; 4 : 70-74. ( PubMed ) 8. Thoma K , Heckenmüller H . Effect of film formers and plasticizers on stability of resistance and disintegration behaviour. Part 4: pharmaceutical-technological and analytical studies of gastric juice resistant commercial preparations [in German]. Pharmazie 1987; 42 : 837-841. ( PubMed ) 9. Neurath AR , Strick N , Li YY , Debnath AK . Cellulose acetate phthalate, a common pharmaceutical excipient, inactivates HIV-1 and blocks the coreceptor binding site on the virus envelope glycoprotein gp120. BMC Infect Dis 2001; 11 : 17. ( PubMed ) 10. Neurath AR , Strick N , Jiang S , et al . Anti-HIV-1 activity of cellulose acetate phthalate: synergy with soluble CD4 and induction of 'dead-end' gp41 six-helix bundles. BMC Infect Dis 2002; 21 : 6. ( PubMed ) 11. Sakellariou P , Rowe RC , White EFT . The thermomechanical properties and glass transition temperatures of some cellulose derivatives used in film coating. Int J Pharm 1985; 27 : 267-277. 12. Callahan JC , Cleary GW , Elefant M , et al . Equilibrium moisture content of pharmaceutical excipients. Drug Dev Ind Pharm 1982; 8 : 355-369. 20. General References 1. Doelker E . Cellulose derivatives. Adv Polym Sci 1993; 107 : 199-265. 2. FMC Biopolymer . Technical literature: Aquacoat cPD, cellulose acetate phthalate aqueous dispersion, 1996. 3. Obara S , Mcginty JW . Influence of processing variables on the properties of free films prepared from aqueous polymeric dispersions by a spray technique. Int J Pharm 1995; 126 : 1-10. 4. O'Connor RE , Berryman WH . Evaluation of enteric film permeability: tablet swelling method and capillary rise method. Drug Dev Ind Pharm 1992; 18 : 2123-2133. 5. Raffin F , Duru C , Jacob M , et al . Physico-chemical characterization of the ionic permeability of an enteric coating polymer. Int J Pharm 1995; 120 2 : 205-214. 6. Wyatt DM . Cellulose esters as direct compression matrices. Manuf Chem 1991; 62 12 : 20, 21, 23.

NF Hypromellose Phthalate

HPMCP

Enteric Coating Material An enteric coating agent is used to protect drugs from degradation by gastric acid or to present them from causing side effects in the stomach. HPMCP (hydroxypropyl methylcellulose phthalate), since its introduction into the market in 1971 as a cellulose derivative for enteric coating, has been demonstrated to be effective by many researchers and is widely used as an enteric coating agent by the pharmaceutical industry. HPMCP has been admitted into the U.S. National Formulary (US/NF). European Pharmacopeia (EP), and Japanese Pharmacopeia (JP).

The chemical structure of HPMCP is a phthalic half ester of hvdroxypropyl methylcellulose, and the threshold pH value for rapid disintegration of HPMCP can he controlled by varying the phthalyl content. Two types of HPMCP with different solubility. HP-55 and HP-50, are available. Moreover HP-55S, a special type of HP-55 which is distinguished by its higher molecular weight, higher film strength and higher resistance to simulated gastric fluid, has also been introduced. A suitable grade of HPMCP for a particular purpose should be selected in accordance with the properties of the formulations.

We are continuing our efforts to improve the quality of our products and to develop new application technologies to satisfy the needs of our customers. For further technical information. refer to a separate publication “Technical Information”.

Designation and structural formula of HPMCP

Designation Hypromellose Phthalate (HPMCP) Substitution Type 2910(USP) Substitution Type 2208(USP) Admissions to compendia USP, EP Chemical name Cellulose, 2-hydroxypropyl methyl ether (CAS 9004-65-3) Trade name Pharmacoat

   Grade   Nominal Phthalyl

Content pH solubility in McIlvaine's Buffer Solution Labelled Viscosity (cSt)* HPMCP 50 24% ≥5.0 55 55 31% ≥5.5 40 55S 170

Note: * 10 wt.% in a mixture of equal weights of Methanol and Methylene Chloride according to the USP/NF measuring method.

Physico-chemical properties 1) Real specific gravity 1.28 2) Apparent density 0.20~0.40g/cm3 tapped

4) Molecular weight and molecular weight distribution The weight-average molecular weight (Mw), number-average molecular weight (Mn) and the ratio of Mw to Mn (Mw/Mn) of HPMCP determined by the gel-permeation chromatography (GPC) method are shown in Table 1.

Table 1: Molecular weight of each type of HPMCP

   HP-55   HP-55S  HP-50

MwX10-4 8.4 13.2 7.8 MnX10-4 2.1 3.6 2.4 Mw/Mn 4.1 4.0 3.3

Note: Polystyrene was used as a standard material

3) Equilibrium moisture content

Fig. 1: Relative humidity and equilibrium moisture content at 25°C for each type of HPMCP

5) Solubility in organic solvents HPMCP dissolves in many kinds of organic solvents. The solubilities of each type of HPMCP at room temperature in typical organic solvents are compared with those of CAP and Shin-Etsu AQOAT (HPMCAS; Hydroxypropyl Methylcellulose Acetate Succinate) in Table 2. HPMCP is different from CAP in that it is soluble in an ethanol/water mixed solvent.

Table 2 Solubility of HPMCP in Organic Solvent

   HPMCP   Shin-Etsu

AQOAT CAP

   HP-55

HP-55S HP-50 AS-MG Acetone O ∆ O O Acetone/water(95:5)* O O O O Acetone/ethanol(1:1)* O O O O Methylene chloride ∆ ∆ ∆ ∆ Methylene chloride/ ethanol(1:1)* O O O O Dioxane O O O O Methanol ∆ ∆ O x Iso-propanol ∆ x x x Ethanol (dehydrated) x x x x Ethanol/water(8:2)* O O O x Ether x x x x

Note ∆:swelling or partially soluble O:soluble x:insoluble *:mixing ratio by weight

6) Properties of HPMCP film The tensile strength, elongation, surface hardness and water vapour permeability of HPMCP films prepared by the casting method are shown in Table 3. Film of 100 µm in thickness, die-cut in the No.1 dumbbell model, was tested after 3 days of conditioning at 25 C and 50°c relative humidity (RH.)The tests were carried out according to JIS K-6301 under conditions of 25°c and 50% R.H. The water vapour permeability was measured at 25°c and 0-75% R.H. Compared with the other HPMCP types, HP-55S had a higher tensile strength due to its higher degree of polymerization.

Table 3 Mechanical Strength, Surface Hardness and Water Vapour Permeability of HPMCP Film

   Tensile

strength (kg/mm2) Elongation (%) Surface hardness (as pencil hardness) Water vapour permeability (g/m2 24hr) HP-55 7.9 5.6 2H-3H 86 HP-55S 8.5 8.3 2H-3H 95 HP-50 7.7 6.1 2H-3H 99

Specifications

The specifications for HPMCP are listed in Table 4 . HPMCP meets all the requirements of US/NF Hydroxypropyl Methylcellulose Phthalate, EP Hypromellose Phthalate or JP Hydroxypropyl Methylcellulose Phthalate.

Shin-Etsu Chemicals performs strict quality control to meet GMP guidelines.

Table 4: Specifications of HPMCP Item/Grade HP-55 HP-55S HP-50

Labelled viscosity (cst)   40      170     55

1. Description and solubility conforms 2. Identification (Infrared Absorption) conforms 3. Viscosity (cst) 32-48 136-204 44-66 4. Water not more than 5.0% 5. Residue on ignition not more than 0.20%

6. Chloride        not more than 0.07%

7. Heavy Metals not more than 0.001%

8. Free phthalic acid      not more than 1.0%

9. Phthalyl content 27.0-35.0% 21.0-27.0%

10. Methoxyl content       18.0-22.0%      20.0-24.0%
11. Hydoroxypropoxyl

content 5.0-9.0% 6.0-10.0%

The test methods of items 1. through 9. are in accordance with the US/NF monograph for Hydroxypropyl Methylcellulose Phthalate. Items 10. and 11. are Shin-Etsu specifications in which the test methods are in accordance with the US/NF monograph for Hydroxypropyl Methylcellulose.

Application Examples Although HPMCP was developed and used originally as an enteric coating agent, its favourable properties have led to extension of its range of applications into other fields, including sustained- release preparations, binders and microcapsule bases. In the above-mentioned applications, HPMCP is usually used alone, but can be used in combination with other polymers, as in the case of the sustained-release preparations. The descriptions of HPMCP given here apply mainly to coating applications.

• Solvents for HPMCP The following mixed solvents are used in general: methylene chloride/ethanol, acetone/ethanol (1:1 by weight). ethanol/water (8:2 for HP-55, 8.5:1.5 for HP-55S. 7:3 for HP-50 by weight).

Pigment

Pigments such as titanium dioxide and lakes are usually used. A remarkable decrease in the simulated gastric fluid resistance may sometimes be observed, especially when titanium dioxide is added to HPMCP in an amount of 10 wt. or more (based on HPMCP).

• Plasticizer Triethyl citrate is effective, but other plasticizers including polyethylene glycol, cetanol, fats and oils such as olive oil, castor oil and monoglycerides of fatty acids can also be used, alone or in combination. The addition of these plasticizers in the amount of 5-10 wt.% (based on HPMCP) may be effective to delay crack generation in the film or to improve the simulated gastric fluid resistance of the coating agent.

• Others During the coating operation on granules, the fluidity of particles is often impaired by static electricity. This may be greatly improved by the addition of about 10 wt.% of water to the solvent.

The addition of talc is effective to prevent adhesion of granules and tablets during coating, and may shorten the coating time.

1) Selection of HPMCP type

In selecting the type of HPMCP, it is recommended to take the following points into account: HP-55 is applicable as a general enteric coating agent. HP-55S, because of its higher degree of polymerization compared with HP-55, tends to have higher solution viscosity, higher mechanical strength of the film and higher simulated gastric fluid resistance of the coating formulation. These characteristics are effective in reducing the necessary amount for coating and in preventing crack generation in film applied to fragile tablets and granules. HP-5O can be dissolved at a lower pH value and is therefore applicable to preparations which are designed to disintegrate in the upper part of the small intestine.

2) Concentration of coating solution

The optimal concentration of the coating solution is different depending on the type of solvent, coating apparatus, dosage form, etc. However, the concentration ranges shown in Table 5 are generally appropriate for coating.

Table 5: Suitable Concentration Ranges of Coating Solution

Type of Coating/Agent HP-55 or HP-50 HP-55S Tabet Coating 6-10 wt.% 5-8 wt.% Granule Coating 5-7 wt.% 4-6 wt.%

Packaging 50kg net: Double layered polythene bag in fibre drum 1 kg net: Double layered polythene bag

The molecular weight of hypromellose phthalate (HPMCP), a polymer used for enteric coating, was determined using size exclusion chromatography with a multi-angle laser light scattering detector. The values of weight-average molecular weight (Mw) of commercially available grades (HP-55, HP-55S, and HP-50) were 45600, 60200, and 37900, respectively. Their inter-day precisions expressed in terms of the coefficient of variation were less than 3%. A correlation curve between Mw and solution viscosity was prepared so that Mw could be easily estimated from the solution viscosity measured by the compendial method.