Quantifying Hidden Lactose In Drugs Biology Essay

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To identify and quantify the amount of lactose used as an excipient in medications that may be taken for the treatment of inflammatory bowel disease and other gastro-intestinal disorders. To assess if alternative 'lactose-free' medications are available for patients with hypolactasia and co-existing GI conditions

6.2: INTRODUCTION

Excipients are defined as the constituents of the pharmaceutical form that is taken by or administered to the patient, other than the active substance(1). They have a variety of purposes, including the improvement of appearance, bioavailability, stability, and palatability of the product. Excipients frequently make up the majority of the mass or volume of drug formulations. These pharmaceutical adjuvants are usually considered to be inert and are said to have no effect on the intended action of the therapeutically active ingredients(1). They are listed in the Medicines Compendium [MC] but not in the British National Formulary [BNF] and are not generally quantified.

Lactose is one of the most widely used excipients by the pharmaceutical industry(2). There are many reasons for its popularity as lactose is perceived to be inert, relatively inexpensive, and non-toxic. It is also chemically stable and has no tendency to react with the active ingredient or other components of a formulation(2). Lactose is also freely soluble in water and it is very palatable providing sweetness without any aftertaste(1, 2). Lactose has a long history of being utilised within many of the successful formulations world-wide including dry powder inhalers, tablets, capsules and sachets.

It has been estimated that lactose is a component of about 20% of prescriptions and 6% of over-the-counter medications(3). In the Italian Physician's Desk Reference there are at least 950 of about 2900 available oral drugs [about 33%] containing lactose as an excipient. Amongst these, capsule/tablet formulations contain, when specified, no more than 400 mg of lactose. Sometimes, labels of these medications warn that their administration is not recommended in people with lactase deficiency(4).

Many of the drugs used in the treatment of Inflammatory Bowel Disease [IBD] contain lactose as an excipient. Patients with IBD also have co-existent gastrointestinal conditions such as dyspepsia, Irritable Bowel Syndrome [IBS] etc and may use drugs to control symptoms that contain lactose as an excipient. In patients with concurrent hypolactasia, the use of medications that contain lactose may be of clinical significance.

6.3: METHODS

Medications used for the treatment of GI disorders or symptoms were identified from the BNF [Vol. 53 March 2007]. The presence of lactose in each formulation was assessed by referring to the 2007 edition of the MC. A selection of these medications was obtained from the hospital pharmacy and analysed for lactose content using high performance liquid chromatography [HPLC].

HPLC was performed using a Kontron HPLC system. Carbohydrates were separated using a Thames Resek Pinnacle II Amino [NH2] 5 150x4.6mm HPLC column [cat. 9217565] preceded by a Phenomenex guard column [containing NH2 [amino, aminopropyl] 4mmx3.0mm ID cartridge filter [cat. KJ 0-4282]. The column was pre-heated to 35C using a Jones chromatography column heater. The carbohydrates were detected using a Shodex RA101 refractive index detector set at 32 or 64RIU at 35C. Mobile Phase was 75% acetonitrile 25% HPLC water [v/v] filtered through a 0.45 nylon filter and degassed prior to use. The mobile phase flow rate was 1.0 mls/min. -Lactose [L-3625], D [-] Glucose [G7021], Fructose [F2543], Sucrose [S-7903], Maltose [M-5885] was purchased from Sigma. HPLC grade Acetonitrile [A/0626/17] and HPLC water [W/0106/17] was purchased form Fisher Scientific Ltd. 0.08M Phosphate buffer was prepared at pH 7.3, pH 4.6 and pH 4.0 by dissolving 1.4g anhydrous dibasic sodium phosphate [Na2HPO4] and 9.68g monobasic sodium phosphate monohydrate [NaH2PO4.H2O] in 750mls of HPLC water. The pH was checked and adjusted as necessary. The buffer solution was then made up to 1 litre with HPLC water.

6.3.1: SAMPLE PREPARATION

Pharmaceutical preparations in tablets, powders or capsule form were received in the laboratory within their original packing. They were crushed with a pestle and mortar and then transferred to a universal container where they were rehydrated or diluted in 5mls of phosphate buffer pH 7.3. This was then mixed on a flat bed rotor and incubated overnight at 4°C or until dissolved. The sample mixture was then centrifuged for 10 minutes at 2500rpm before the supernatant was filtered thorough a 0.45 filter. Two ml of the supernatant was mixed with 2ml of acetonitrile [v/v] and mixed. The mixture was then left overnight at 4ï‚°C, before microfuging it at 13,000rpm for 5 minutes and filtering the supernatant through a 0.45 filter. It was then passed through a previously primed LC-NH2 SPE tube [As per manufacturers instructions, Cat.504483 Supelco] using positive pressure [flow approximately 1ml/12seconds]. Finally the filtrate was dispensed into HPLC auto sampler vials and analyzed for lactose content.

The concentration of lactose and other sugars including glucose, fructose, sucrose and maltose was determined by reference to the calibrator peak height. The peak data was integrated using Kroma 2000 chromatography software and quality control was performed with known carbohydrate solutions(5). In order to calculate the carbohydrate concentration the following formula was used. Sugars, g/g = [Test Peak Height/Standard Sugar Peak Height] x buffer added to drug in l/ [amount of sample injected x Sugar Concentration g]/test portion weight in grams.

6.4: RESULTS

I selected in the MC drugs used in the treatment of IBD that were identified as having lactose present or absent. Drugs from each of the sub-sections listed in the Gastro-Intestinal chapter of the British National Formulary [BNF] were also selected and their lactose content analysed. As some medications are available from multiple manufacturers, selections of drug preparations were obtained for assessment. In addition to those used in GI disorders, I also analysed drugs that can be used for a variety of symptoms including abdominal ones e.g. analgesics and anti-depressants.

A total of 71 preparations were obtained and analysed, of these 31 [43.7%] preparations contained lactose whilst 40 [56.3%] were lactose free. The results of this HPLC based methodology correlated exactly with the summary of product characteristics in the MC i.e. it detected lactose in all formulations which were stated to contain it and did not measure lactose in those where it was not mentioned. To ensure that the methodology was robust and the results obtained were reproducible, three drugs were randomly selected and re-analysed on three different occasions. This shows consistency with the quantity of lactose detected per tablet for Prednisolone [Pfizer] 31±1 mg, Azathioprine [GlaxoSmithKline] 71±1 mg & Colofac [Solvay] 95±2 mg.

17 drugs used in the treatment of IBD were tested of those 8 contained lactose and lactose was not identified in the other 9. In preparations where lactose was detected, it ranged from 28.9 mg [equivalent to 0.6mls of milk] in a single 2.5 mg tablet of Methotrexate [Cyanamid] to 600mg of lactose [equivalent to 12.7mls of milk] in a 3mg capsule of Budenofalk [Dr Falk]. The maximum amount of lactose that patients may consume per day from the ingestion of a single drug used in the treatment of IBD was 1200mg [equivalent to 26mls of milk] with Asacol MR 4800 mg a day.

In other preparations where lactose was detected, it ranged from just 4mg [equivalent to 0.2mls of milk] in single 40mg capsule of Losec to 125mg [equivalent to 2.7mls of milk] in Immodium [Janssen-Cilag] 2mg. The maximum amount of lactose that patients may consume per day from the ingestion of GI drugs ranged from 4mg/day [0.2mls of milk] in Losec 40mg to 10.2 grams/day [equivalent to 216mls of milk] when the maximum BNF quoted daily dosage, 150ml, of Lactulose is ingested. The chromatogram produced by the standard sugars is shown in figure 6.1, Loperamide 2mg [Tillomed] with lactose is shown in figure 6.2, Imodium Instant melts [McNeil UK] which also has Loperamide with no lactose in figure 6.3 and figure 6.4 shows Codeine phosphate 30mg [Teva UK] which contains lactose.

Figure 6.1: Separation of standard sugars by HPLC, on the X-axis is time at which these sugars appear during chromatography and Y-axis is the amplitude which depends on the quantity of the sugar preset.

Fructose Sucrose Lactose

Glucose Maltose

Figure 6.2: A chromatogram showing Loperamide [Tillomed] containing Lactose, on the X-axis is time at which these sugars appear during chromatography and Y-axis is the amplitude which depends on the quantity of the sugar preset.

Lactose

Figure 6.3: A chromatogram showing another formulation of Loperamide Imodium Melts [Mc Neil UK] without Lactose, on the X-axis is time at which these sugars appear during chromatography and Y-axis is the amplitude which depends on the quantity of the sugar preset.

Figure 6.4: A chromatogram showing Codeine Phosphate [Teva UK] containing Lactose in addition has Fructose, on the X-axis is time at which these sugars appear during chromatography and Y-axis is the amplitude which depends on the quantity of the sugar preset

Lactose

Fructose

The results are presented in tables 6.1 to 6.6 using similar subgroups as the BNF i.e. based on the actions and indications of a drug. For those with lactose present, the results are summarised for each formulation in tables 6.1 to 6.4, giving potential daily intake of lactose if maximum recommended daily dosages is ingested. For each indication, lactose free alternatives were identified and these are listed in Tables 6.5 & 6.8. The results show that lactose is present in drugs used for all GI symptoms but lactose free alternatives are available for every indication. By taking the maximum recommended daily dosage, it is possible to be exposed to quite large amounts of lactose through the ingestion of drugs alone - this is in addition to what is ingested in the diet. The tables show that 1,000mg per day of lactose [equivalent to 21.2mls of milk] would be taken if 16mg of Imodium [Janssen-Cilag] were ingested for diarrhoeal or functional abdominal conditions ; 450mg [9.5mls milk] of lactose would be ingested if 80mg Domperidone [Winthrop] was taken as an anti-emetic ; 1,800mg [38.1ml of milk] if 9mg of Budenofalk [Dr Falk] was taken for active IBD or the treatment of microscopic colitis and by taking 150ml of Lactulose a patient would ingest 10,200mg of lactose [216mls milk] each day.

Table 6.1: Antispasmodics and drugs altering GI motility that contain lactose

Group Name

Generic name

Brand Name & Dosage

Manufacturer

Lactose per tablet [mg]

Maximum no of tablets per day

Lactose present if maximal daily dose ingested [mg]

Equivalent amount of milk[mls]

Antimuscarinics

Dicycloverine Hydrochloride

Merbentyl 10mg

Florizel

74

6

444

9.4

Propantheline Bromide

Pro-Banthine 15 mg

Concord

38

8

304

6.4

Other Antispasmodics

Mebeverine Hydrochoride

Colofac 135 mg

Solvay

95

3

285

6.0

Mebeverine Hydrochloride 135 mg

Merck Generics

99

3

297

6.3

Anti-motility Drugs

Codeine Phosphate

Codeine Phosphate 30mg

Teva UK

46

8

368

7.2

Loperamide Hydrochloride

Imodium 2mg

Janssen-Cilag

125

8

1000

21.2

Imodium 2mg

Tillomed

108

8

864

18.3

Table 6.2: Antacids & Ulcer healing Drugs that contain lactose

Group Name

Generic name

Brand Name & Dosage

Manufacturer

Lactose per tablet [mg]

Maximum no of tablets per day

Lactose present if maximal daily dose ingested [mg]

Equivalent amount of milk[mls]

PPI

Omeprazole

Losec 40 mg

AstraZeneca

4

2

8

0.2

Lansoprazole

Zoton Fastab 30 mg

Wyeth

28

2

56

1.2

Anti-emetics

Domperidone

Domperidone 10 mg

Winthorp

56

8

450

9.5

Metoclopramide

Metoclopramide 10 mg

APS

71

3

213

4.5

Prochlorperazine

Prochlorperazine 5mg

IVAX

70

6

420

8.9

Others

Vitamins

Valupak Multivitamins

BR Pharmaceuticals

38

2

76

1.6

Table 6.3: Drugs for IBD that contain lactose

Group Name

Generic name

Brand Name & Dosage

Manufacturer

Lactose per tablet [mg]

Maximum no of tablets per day

Lactose present if maximal daily dose ingested [mg]

Equivalent amount of milk[mls]

Aminosalicylates

Mesalazine

Asacol MR 400mg

Proctor & Gamble

75

6

450

9.5

Mesren MR 400mg

Ivax

77

6

462

9.8

Corticosteroids

Budesonide

Budenofalk 3mg

Dr Falk

600

3

1800

38.1

Prednisolone

Delta-cortil 5mg

Pfizer

31

12

372

7.9

Prednisolone 2.5mg

Alpharm

56

24

1344

28.5

Immuno-suppressants

Azathioprine

Imuran 50mg

Glaxo

SmithKline

71

3.5

248.5

5.3

6 Mercapto-purine

Puri-Nethol 50mg

Glaxo

SmithKline

61

2

122

2.6

Methotrexate

Methotrexate 2.5mg

Cyanamid

28.9

6

173.4

3.7

Table 6.4: The other drugs that may be used in GI patients that contain lactose

Group Name

Generic name

Brand Name & Dosage

Manufacturer

Lactose per tablet [mg]

Maximum no of tablets per day

Lactose present if maximal daily dose ingested [mg]

Equivalent amount of milk[mls]

Laxatives

Bowel cleansing solutions

Picolax

Ferring

4

2 sachets

8

0.2

Senna

Senokot 7.5 mg

Reckitt Benckiser

16

4

64

1.4

Lactulose

Lactulose

Novartis

340mg/5ml

150ml

10200

216.1

Methylcelluose

Celevac 500 mg

Shire

27.7

12

332

7.0

Bisacodyl

Dulco-Lax 5 mg

Boehringer-Ingelheim

41

2

82

1.7

Ursodeoxycholic acid

Ursodeoxycholic acid

Destolit 150mg

Norgine

78

7

546

11.6

Others

Pancreatin

Pancrex V Tablets

Paines & Byrne

54

45

2430

51.5

Tricyclic antidepressants

Amitryptiline 10mg

Teva UK

43

20

860

18.2

Allegron 10mg

King Pharmaceuticals

38

15

570

12.1

SSRI

Citalopram 20mg

Ranbaxy

45

3

135

2.9

Table 6.5: Antispasmodics and drugs altering GI motility that are lactose free.

Group Name

Generic name

Brand Name & Dosage

Manufacturer

Antispasmodics

Mebeverine hydrochloride

Colofac MR

Solvay

Alverine Citrate

Spasmonal

Norgine

Hyoscine Butylbromide

Buscopan

Boehringer Ingelheim

Peppermint Oil

Colpermin

Pharmacia

Mintec

Shire

Anti-motility Drugs

Loperamide

Imodium Instant Melts

McNeil UK

Co-Phenotrope

Lomotil 2.5/0.025

Goldshield

Table 6.6: Antacids & Ulcer healing Drugs that are Lactose free.

Group Name

Generic name

Brand Name & Dosage

Manufacturer

H2-Receptor antagonists

Ranitidine

Zantac

GlaxoSmithKline

Cimetidine

Dexcel 200mg

Dexcel

Nizatidine

Axid

Flynn

Famotidine

Pepcid

MSD

Complexes

Sucralfate

Antepsin

Chugai

Prostaglandin analogues

Misoprostol

Cytotec

Pharmacia

PPI

Pantoprazole

Protium

Altana

Rabeprazole

Pariet

Janssen-Cilag, Eisai

Esomeprazole

Nexium

AstraZeneca

Lansoprazole

Zoton

Wyeth

Omeprazole

Losec MUPS

AstraZeneca

Anti-emetics

Prochlorperazine

Buccastem

Reckitt Benckiser

Table 6.7: Lactose free alternatives for the drugs used in the management of IBD

Group Name

Generic name

Brand Name & Dosage

Manufacturer

Aminosalicylates

Mesalazine

Pentasa 500mg tablets

Ferring

Ipocol 400mg

Sandoz

Salofalk 250mg tablets

Dr Falk

Balsalazide

Colazide 750 mg

Shire

Olsalazine

Dipentum 250/500mg

Celltech

Sulfasalazine

Salazopyrin-EN 500mg

Pharmacia

Budesonide

Entocort CR 3mg

AstraZeneca

Immunosuppressant's

Ciclosporin

Neoral 100mg

Novartis

Table 6.8: The other drugs that may be used in GI patients that are lactose free.

Group Name

Generic name

Brand Name & Dosage

Manufacturer

Laxatives

Docusate Sodium

Dioctyl 100mg

Schwarz

Macrogols

Movicol

Norgine

Ursodeoxycholic acid

Ursodeoxycholic acid

Ursofalk 250mg

Dr Falk

Ursogal

Galen

Bile acid sequestrants

Colestyramine

Questran

Bristol-Myers Squibb

Pancreatin

Pancreatin

Creon 10,000 & 25,000

Solvay

Pancrex V 125mg capsules

Paines& Byrne

Analgesics

Paracetamol

Paracetamol 500mg

Tesco

Paracetamol 500mg caplets

Value Health

Co-Codamol

Co-Codamol 8/500

Alpharm

Co-Codamol 30/500

CP

Co-Dydramol

Co-Dydramol

M&A Pharmaceuticals

SSRI

Fluoxetine

20mg

Tillomed

Paroxetine

20mg

Sandoz

6.5: DISCUSSION

These results clearly show that lactose is present in medications prescribed for the treatment of IBD and in a wide range of GI disorders. This could lead to symptoms of lactose intolerance in susceptible individuals. Doctors may not know that the medicines they prescribe contain lactose as the details of the excipients in medicines are not available in the BNF [the most trusted guide used by doctors in the UK](6). Although the European Commission guidelines of 2003 state that by law, manufacturers must list the excipient in the patient leaflets; they are however not required to quantify the amount present. A summary of the product characteristics of drugs are listed in the Medicines Compendium; this is used by pharmacists to find information about excipients but all the versions of the drug are not listed in MC or ECM [electronic version of the compendium of medicine]. It should also be noted that neither the MC nor the ECM are widely used by doctors and allied health professionals - and many maybe not even aware of their existence. I feel that the presence and quantity of lactose should be displayed in a prominent place to alert both the prescriber and the patient e.g. in the BNF or the drug packet.

Clinicians may not feel that the amount of lactose present in drug formulation is enough to contribute towards the symptoms of a patient. However sensitivity to lactose and the severity of symptoms it causes varies widely in patients. Petrini et al. observed two lactase-deficient women with Graves' disease who experienced severe diarrhoea after ingestion of propylthiouracil [amount of lactose not specified] and methimazole [about 60 mg of lactose] (7). Brandstetter et al. described the case of a young woman with lactase deficiency who complained of gastrointestinal symptoms after inhalation of a capsule of cromolyn sodium containing 20 mg of lactose(8). Lieb et al. described two patients with lactose malabsorption in whom abdominal cramps and diarrhoea developed after a medication with lithium carbonate and flurazepam hydrochloride [unspecified dosages of lactose] was started(9).Several different types of medications have been implicated to cause lactose sensitivity in susceptible individuals(7-12).

Due to variations in tolerance to lactose by individuals a single threshold of lactose for all lactose sensitive individuals cannot be determined. Despite this it has been widely reported that most individuals can tolerate up to 11.8g of lactose per day [250ml of milk](13-15). Studies have also shown that symptoms can be precipitated by consumption of 3 to 5g of lactose(14, 16, 17). But in highly sensitive individuals it has been reported that the symptoms may occur after ingestion of as little as 200mg of lactose(17) and different types of medications have been shown to cause Lactose sensitivity in addition affects compliance(7-12, 18). This could easily be ingested by taking a single 3mg tablet of Budenofalk [Dr Falk] which contains 600mg of lactose. Patients often take more than one medication for their condition and so may have a cumulative exposure. For GI problems I have identified that the ingestion of certain medications, either alone or in combination may result in a patient consuming of over 10 grams of lactose a day in addition to that taken in their normal diet. However, none of the medications used primarily for IBD alone or in combination would result in intake greater than 10g per day of lactose. However, they may also be on other lactose containing medication for co-existent illness for e.g. hypertension.

The drugs used in treatment of IBD like 5-ASA preparations & Budesonide are formulated to deliver the active ingredients topically to the distal small bowel and colon after oral ingestion. This is achieved in by a pH dependent release mechanism or through bacterial degradation. I have shown that some of these preparations contain lactose and as they remain intact in the upper GI tract they will also deliver undigested lactose to the colon where they could give the symptoms of LI. Of the Nine 5-ASA drug preparations used in the treatment of IBD tested, two contained lactose and lactose was not identified in the other seven. The preparations where lactose was detected, were Asacol MR [400mg] 75mg of lactose [equivalent to 1.6mls of milk] and Mesren MR [400mg] 77mg of lactose [equivalent to 1.6mls of milk] in a single tablet The maximum amount of lactose that patients may consume per day from the ingestion of 5 ASA drugs used in the treatment of IBD was 1200mg [equivalent to 26mls of milk] with Asacol MR 4800 mg a day. The other 7 preparations Pentasa 500mg, Ipocol 400mg, Salofalk 250mg, Colazide 750mg, Dipentum 250 & 500mg and Salazopyrin-EN 500mg. Since the completion of this study the formulation of Asacol MR 400 mg has been changed by the manufacturer and it has now become lactose free.

Drugs that impair mucosal function or modifies its structure may have an effect on lactase expression or on its activity. The broad spectrum antibiotic neomycin has been shown to reduce lactase activity(19). Fixed food eruptions have been caused by lactose identified after oral administration of four unrelated drugs(18). These effects of lactose containing drugs can also affect compliance with medications(10). Lactose was shown to induce bronchospasm in asthmatics(20).

Improved lactose handling occurs when oro-caecal transit time is prolonged. Drugs which affect gastro-intestinal motility either directly or as a side effect could have an influence on the digestion and absorption of lactose. In clinical practice it is very common to find lactose malabsorbers who believe that the ingestion of a very small amount e.g. in white coffee can produce gastrointestinal symptoms. Frequently encouraged by news media or advised by their family physicians, they start a restrictive lactose-free diet. Moreover, in some recent scientific publications, authors suggest caution with these medications or, even, warn not to use them altogether (10, 21, 22). The onset of gastrointestinal symptoms after ingestion of a lactose containing drug in lactose maldigesters has been described but only in a limited number of case reports (7-9, 12), and there are no large population or randomized control studies.

The primary form of therapy for lactose sensitivity after diagnosis is to adjust the amount of lactose containing foods in the diet accordingly. The results here show that patients on a clinically restricted diet may inappropriately take medications that contain lactose in amounts that could cause symptoms. The details of excipients in medications are not readily accessible by doctors and other health professionals. They may also be unaware that lactose free alternatives are available. It should be noted that liquid preparations of most drugs are lactose free and provide another alternative form of treatment in those with known lactose sensitivity. The clinical management of LS may be confused by not taking into account "hidden" lactose in foods and medications. Symptoms may occur in individuals, which could be contributed by this "hidden" lactose, this is often overlooked by healthcare professionals(21).

6.6: CONCLUSION

Assessment of lactose derived from medications should be considered in addition to dietary sources for both primary and secondary hypolactasic patients. In such patients the use of alternative 'lactose free' medications may avoid exacerbating symptoms in GI disorders such as IBD or IBS. I propose that lactose free medications should be prescribed to patients with a high risk of LS due to ethnicity, in those whose symptoms worsen with no objective evidence of disease deterioration, & in those who develop new symptoms after commencing medications. Ideally, in these groups of patients, tests to diagnose LS should be carried out to aid both dietary advice and the prescription of medications(23). The significance of the presence of lactose in the medications need to be further ascertained in a randomized control trial but in the interim, observational data should be collected from patients with LS and GI conditions to see if they have symptomatic benefit from using lactose free alternatives.

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