lactose are largely attributed to lactose intolerance, which occurs in individuals with a deficiency of the intestinal enzyme lactase.(22–25) This results in lactose being undigested and may lead to cramps, diarrhea, distension, and flatulence. In lactose- tolerant individuals, lactase hydrolyzes lactose in the small intestine to glucose and galactose, which are then absorbed. Lactase levels are normally high at birth, and levels decline rapidly in early childhood. Malabsorption of lactose (hypo- lactasia) may occur at an early age (4–8 years) and varies among different ethnic groups. Lactose is excreted unchanged when administered intravenously.

The symptoms of lactose intolerance are caused by the osmotic effect of the unabsorbed lactose, which increases water and sodium levels in the lumen. Unabsorbed lactose, upon reaching the colon, can be fermented by colonic flora, which produces gas, causing abdominal distension and discomfort. A lactose tolerance test has been developed based on the measurement of blood glucose level and the hydrogen level in the breath. However, its usefulness has been questioned as the test is based on a 50 g dose of lactose.

Approximately 10–20% of lactose-intolerant individuals, in two studies, showed clinical symptoms of intolerance after ingestion of 3–5 g of lactose.(22,23) In one of the studies,(22) 75% of the subjects had symptoms with 12 g of lactose (equivalent to 250 mL of milk). In another,(23) eight out of 13 individuals developed diarrhea after the administration of 20 g of lactose, and nine out of 13 after the administration of 25 g.

Lower doses of lactose produce fewer adverse effects, and lactose is better tolerated if taken with other foods. As a result, there is a significant population with lactose malabsorption who are still able to ingest normal amounts of lactose, such as that in milk, without the development of adverse side effects.(24)

Most adults consume about 25 g of lactose per day (500 mL of milk) without symptoms.(25,26) When symptoms appear, they are usually mild and dose-related. The dose of lactose in most pharmaceuticals seldom exceeds 2 g per day. It is unlikely that severe gastrointestinal symptoms can be attributed to the lactose in a conventional oral solid-dosage form, especially in adults who have not previously been diagnosed as severely lactose-intolerant. However, anecdotal reports of drug-induced diarrhea due to lactose intolerance have been made following administration of pharmaceutical preparations containing lactose.

It has also been suggested that lactose intolerance may have a role in irritable bowel syndrome, but this role is currently unclear.(27)

In the past, there have been concerns over the transmissible spongiform encephalopathies (TSE) contamination of animal- derived products. However, in the light of current scientific knowledge, and irrespective of geographical origin, milk and milk derivatives are reported as unlikely to present any risk of TSE contamination; TSE risk is negligible if the calf rennet is produced in accordance with regulations.(28)

LD50 (rat, IP): >10 g/kg LD50 (rat, oral): >10 g/kg LD50 (rat, SC): >5 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Excessive generation of dust, or inhalation of dust, should be avoided.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (IM, IV, and SC injections; oral capsules and tablets; inhalation preparations; rectal, transdermal, and vaginal preparations). Included in nonparenteral and parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

Lactose, anhydrous; lactose, spray-dried.

Comments

A number of different grades of lactose are commercially available that vary in their physical properties and many studies have been reported in the literature comparing the behavior of these various materials in different formulations.(6,9–11) A number of co-processed excipients which contain lactose are available for direct-compression applications: co-processed lactose and starch (Starlac, Meggle/Roquette Fre´res),(29) lactose and microcrystalline cellulose (Microcelac, Meggle);(30) lactose and cellulose powder (Cellactose, Meggle),(31,32) lactose, povidone, and crospovidone (Ludipress, BASF).

Lactose may exhibit complex thermoanalytical transitions because of its several crystalline, as well as amorphous, forms. Differential scanning calorimetry (DSC) can be used effectively to characterize the composition.(33–35) For example, a-lactose becomes anhydrous at approximately 1208C. a-Lactose mono- hydrate may also contain a small quantity of the b-form.

The CAS number for lactose monohydrate, cycloic form is [10039-26-6]; and the CAS number for lactose monohydrate, open form is [64044-51-5]. A specification for lactose is included in the Food Chemicals Codex (FCC).

The EINECS number for lactose is 200-559-2.

Specific References

Alpar O, Hersey JA, Shotton E. The compressions properties of lactose. J Pharm Pharmacol 1970; 22 (Suppl.): 1S–7S.

Bolhuis GK, Lerk CF. Comparative evaluation of excipients for direct compression, I. Pharm Weekbl 1974; 109: 945–955.

Vromans H, de Boer AH, Bolhuis GK, et al. Studies on the tableting properties of lactose: the effect of initial particle size on binding properties and dehydration characteristics of a-lactose mono- hydrate. In: Rubinstein MH, ed. Pharmaceutical Technology: Tableting Technology, vol. 1. Chichester: Ellis Horwood, 1987: 31–42.

Thwaites PM, Mashadi AB, Moore WD. An investigation of the effect of high speed mixing on the mechanical and physical properties of direct compression lactose. Drug Dev Ind Pharm 1991; 17: 503–517.

Riepma KA, Dekker BG, Lerk CF. The effect of moisture sorption on the strength and internal surface area of lactose tablets. Int J Pharm 1992; 87: 149–159.

C¸ elik M, Okutgen E. A feasibility study for the development of a prospective compaction functionality test and the establishment of a compaction data bank. Drug Dev Ind Pharm 1993; 19: 2309– 2334.

Lerk CF. Consolidation and compaction of lactose. Drug Dev Ind Pharm 1993; 19: 2359–2398.

Otsuka M, Ohtani H, Otsuka K, Kaneniwa N. Effect of humidity on solid-state isomerization of various kinds of lactose during grinding. J Pharm Pharmacol 1993; 45: 2–5.

Bolhuis GK, Lerk CF. Comparative evaluation of excipients for direct compression. Pharm Weekbl 1973; 108: 469–481.

Paronen P. Behaviour of some direct compression adjuvants during the tabletting process. STP Pharma 1986; 2(19): 682–688.

Lactose, Monohydrate 395

Zuurman K, Riepma KA, Bolhuis GK, et al. The relationship between bulk density and compactibility of lactose granulations. Int J Pharm 1994; 102: 1–9.

Bernabe I, Di Martino P, Joris E, et al. An attempt at explaining the variability of the compression capacity of lactose. Pharm Technol Eur 1997; 9(1): 42–51.

Hwang RC, Peck GR. A systematic evaluation of the compression and tablet characteristics of various types of lactose and dibasic calcium phosphate. Pharm Technol 2001; 25(6): 54–68.

Steckel H, Markefka P, TeWierik H, Kammelar R. Functionality testing of inhalation grade lactose. Eur J Pharm Biopharm 2004; 57: 495–505.

Kawashima Y, Serigano T, Hino T, et al. Effect of surface morphology of carrier lactose on dry powder inhalation property of pranlukast hydrate. Int J Pharm 1998; 172: 179–188.

Larhrib H, Zeng XM, Martin GP, et al. The use of different grades of lactose as a carrier for aerosolised salbutamol sulfate. Int J Pharm 1999; 191: 1–14.

Kibbe AH, ed. Handbook of Pharmaceutical Excipients, 3rd edn. London and Washington, DC: Pharmaceutical Press and American Pharmaceutical Association 2000: 642–643.

Castello RA, Mattocks AM. Discoloration of tablets containing amines and lactose. J Pharm Sci 1962; 51: 106–108.

Hartauer KJ, Guilroy JK. A comparison of diffuse reflectance FT- IR spectroscopy and DSC in the characterization of a drug– excipient interaction. Drug Dev Ind Pharm 1991; 17: 617–630.

Blaug SM, Huang W. Interaction of dextroamphetamine sulfate with spray-dried lactose. J Pharm Sci 1972; 61: 1770–1775.

Eyjolfsson R. Lisinopril–lactose incompatibility. Drug Dev Ind Pharm 1998; 24: 797–798.

Bedine MS, Bayless TM. Intolerance of small amounts of lactose by individuals with low lactase levels. Gastroenterology 1973; 65: 735–743.

Gudmand-Hoyer E, Simony K. Individual sensitivity to lactose in lactose malabsorption. Am J Dig Dis 1977; 22(3): 177–181.

Pray WS. Lactose intolerance. US Pharm 1990; 15(11): 24, 26, 28,

29.

Suarez FL, Savaiano Dennis A. Diet, genetics, and lactose intolerance. Food Technol 1997; 51(3): 74–76.

Suarez FL, Savaiano DA, Levitt MD. A comparison of symptoms after the consumption of milk or lactose-hydrolyzed milk by people with self-reported lactose intolerance. N Engl J Med 1995; 333: 1–4.

Spanier JA, Howden CW, Jones MP. A systemic review of alternative therapies in the irritable bowel syndrome. Arch Intern Med 2003; 163(3): 265–274.

The European Agency for the Evaluation of Medicinal Products. Evaluation of Medicines for Human Use. London, 9 Dec 2002: EMEA/410/01 Rev. 2.

Hauschild K, Picker-Freyer KM. Evaluation of a new coprocessed compound based on lactose and maize starch for tablet formula- tion. AAPS Pharm Sci 2004; 6(2): e16.

Michoel A, Rombaut P, Verhoye A. Comparative evaluation of co- processed lactose and microcrystalline cellulose with their physical



mixtures in the formulation of folic acid tablets. Pharm Dev Technol 2002; 7(1): 79–87.

Reimerdes D, Aufmuth KP. Tabletting with co-processed lactose– cellulose excipient. Manuf Chem 1992; 63(12): 21, 23, 24.

Casalderrey M, Souto C, Concheiro A, et al. A comparison of drug loading capacity of cellactose with two ad hoc processed lactose- cellulose direct compression excipients. Chem Pharm Bull (Tokyo) 2004; 52(4): 398–401.

Chidavaenzi OC, Buckton G, Koosha K, Pathak R. The use of thermal techniques to assess the impact of feed concentration on the amorphous content and polymorphic forms present in spray dried lactose. Int J Pharm 1997; 159: 67–74.

Hill VL, Craig DQM, Feely LC. Characterisation of spray-dried lactose using modulated differential scanning calorimetry. Int J Pharm 1998; 161: 95–107.

Lerk CF, Andreae AC, de Boer AH, et al. Alterations of a-lactose during differential scanning calorimetry. J Pharm Sci 1984; 73: 856–857.

General References

BASF. Technical literature: Ludipress, 2004.

Bolhuis GK, Chowhan ZT. Materials for direct compaction. In: Alderborn G, Nystro¨ m C, eds. Pharmaceutical Powder Compaction Technology. New York: Marcel Dekker, 1996: 459–469.

Borculo Domo Ingredients. Technical literature: Lactochem, 2003. DMV International. Technical literature: Pharmatose, 2003.

Foremost Farms USA. Technical literature: NF Lactose 310, NF Lactose 312, NF Lactose 313, 2004.

Meggle GmbH. Technical literature: Lactose excipients, 2004.

Pearce S. Lactose: the natural excipient. Manuf Chem 1986; 57(10): 77–80.

Quest International Inc. (Sheffield Products). Technical literature: Lactose Monohydrate NF 80M, NF Capsulating, NF Impalpable, 2004.

Rajah KK, Blenford DE, eds. The ALM Guide to Lactose Properties and Uses. The Hague: The Association of Lactose Manufacturers, 1998.

Roquette Fre´res. Technical literature: Starlac, 2004.

Smith IJ, Parry-Billings M. The inhalers of the future? A review of dry powder devices on the market today. Pulm Pharmacol Ther 2003; 16: 79–95.

Authors

S Edge, A Kibbe, K Kussendrager.

Date of Revision

28 August 2005.

Lactose, Spray-Dried

Nonproprietary Names

None adopted.

Synonyms

FlowLac 100; Lactopress Spray-Dried; NF Lactose–316 Fast Flo; NF Lactose–315; Pharmatose DCL 11; Pharmatose DCL 14; Super-Tab Spray-Dried.

Chemical Name and CAS Registry Number

Spray-dried lactose is a mixture of amorphous lactose, which is a 1 : 1 mixture of a-and-b-lactose, and O-b-D-galactopyrano- syl-(1→4)-a-D-glucopyranose monohydrate [64044-51-5].

Empirical Formula and Molecular Weight

C12H22O11 342.30 (for amorphous) C12H22O11·H2O 360.31 (for monohydrate)

Structural Formula

See Lactose, Anhydrous and Lactose, Monohydrate.

Functional Category

Binding agent; directly compressible tablet excipient; tablet and capsule diluent; tablet and capsule filler.

Applications in Pharmaceutical Formulation or Technology

Spray-dried lactose is widely used as a binder, filler-binder, and flow aid in direct compression tableting.

See also Lactose, Monohydrate; Lactose, Anhydrous.

Description

Lactose occurs as white to off-white crystalline particles or powder. It is odorless and slightly sweet-tasting. Spray-dried direct-compression grades of lactose are generally composed of 80–90% specially prepared pure a-lactose monohydrate along with 10–20% of amorphous lactose.

SEM: 1

Excipient: Pharmatose DC 11 Manufacturer: DMV International Magnification: 300×

Voltage: 5 kV

 

SEM: 2

Excipient: Super-Tab Spray-Dried Manufacturer: Lactose New Zealand Magnification: 500×

Voltage: 10 kV

 

Pharmacopeial Specifications

See Section 18.

Typical Properties

Angle of repose: see Table I.

Bonding index: 0.0044 for NF Lactose–315 (compression pressure 54.90 MPa)(a)

Lactose,  Spray-Dried 397

Table I: Typical physical properties of selected commercially available spray-dried lactose.

SEM: 3

Excipient: Lactopress Spray-Dried Manufacturer: Borculo Domo

 

Brittle fracture index: 0.1671 for NF Lactose–315 (compres- sion pressure 54.90 MPa)(a)

Density bulk: see Table I.

Reduced modulus of elasticity: 5648 for NF Lactose–315

(compression pressure 5.49–54.90 MPa)(a)

Tensile strength: 2.368 MPa for NF Lactose–315 (compression pressure 54.90 MPa)(a)

Water content: see Table I.

(a) Methods for characterizing the mechanical properties of compacts of pharmaceutical ingredients are specified in the Handbook of Pharmaceutical Excipients, 3rd edn.(1)

Stability and Storage Conditions

Spray-dried lactose should be stored in a well-closed container in a cool, dry place.

Incompatibilities

See Lactose, Anhydrous and Lactose, Monohydrate.



Method of Manufacture

A suspension of a-lactose monohydrate crystals in a lactose solution is atomized and dried in a spray drier.(2,3) Approxi- mately 10–20% of the total amount of lactose is in solution and the remaining 80–90% is present in the crystalline form. The spray-drying process predominantly produces spherical parti- cles. The compactibility of the material and its flow character- istics are a function of the primary particle size of the lactose monohydrate and the amount of amorphous lactose.(4)

Safety

Lactose is widely used in pharmaceutical formulations as a diluent in oral capsule and tablet formulations. It may also be used in intravenous injections.

Adverse reactions to lactose are largely due to lactose intolerance, which occurs in individuals with a deficiency of the enzyme lactase.

See Lactose, Monohydrate.

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material being handled. Excessive generation of dust, or inhalation of dust, should be avoided.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (IM, IV, and SC injections; oral capsules and tablets; inhalation preparations; rectal, transdermal, and vaginal preparations). Included in nonparenteral and parenteral medicines licensed in the UK.

Related Substances

Lactose, anhydrous; lactose, monohydrate.

Comments

Spray-dried lactose was one of the first direct-compression excipients. Spray-dried lactose typically comprises lactose monohydrate and amorphous lactose (see Section 8); see Lactose, Monohydrate for the relevant pharmacopeial infor- mation.

It has been shown that during the spray-drying process the effects of nozzle orifice diameter and atomization air flow control the droplet size during atomization; however, it has also been demonstrated that increasing feed concentration results in

398 Lactose,  Spray-Dried

Table II: Particle size distribution of selected commercially available spray-dried lactose.

Supplier/grade Percentage less than stated size

 

<32 mm <45 mm <75 mm <100 mm <150 mm <250 mm    

Borculo Domo Ingredients

Lactopress Spray-Dried

—

425

—

30–60(a)

—

565    

Lactopress Spray-Dried 250 — 415 450 30–60 — 598    

DMV International    

Pharmatose DCL 11 — 10 — 40 — 100    

Pharmatose DCL 14 — 10 — 40 — 100    

Foremost Farms

NF Lactose–316 Fast-Flo

—

—

20–40

45–70(a)

—

99.5–100    

NF Lactose–315 — — 25–45 45–70(a) — —    

Meggle GmbH    

FlowLac 100 6 — — 34 — 98    

Lactose New Zealand    

Super-Tab Spray-Dried — — 14 — 52 97    

(a) <106 mm.  

increased shell thickness of hollow particles that are formed.(5) The physical properties of spray-dried lactose produced from alchoholic media are directly affected by the ethanol-to-water ratio in the feed solution. Lactose spray-dried from pure ethanol was shown to be 100% crystalline, whereas lactose spray-dried from pure water was 100% amorphous. Further- more, the surface area of the spray-dried lactose increased as a function of amorphous content.(6) Spray-dried lactoses exhibit good flow properties.(7)

Polyethylene glycol (PEG) 4000, when spray-dried with lactose, has been shown to accelerate the rate and extent of crystallization of lactose.(8) It has also been shown that spray- dried lactose composite particles containing an ion complex of chitosan are suitable for the dry-coating of tablets.(9) Spray- dried lactose and crystallized spray-dried lactose have been evaluated for dry powder inhalation.(10,11) Amorphous spray- dried lactose has also been studied in composites with PVP.(12)

See also Lactose, Anhydrous and Lactose, Monohydrate.

Specific References

Kibbe AH, ed. Handbook of Pharmaceutical Excipients, 3rd edn. London and Washington, DC: Pharmaceutical Press and American Pharmaceutical Association, 2000: 642–643.

Hutton JT, Ellen G, Palmer GM, Valley C. Lactose product and method. United States Patent No. 3,639,170; 1972.

Vromans H, Kussendrager KD, Van Den Biggelaar HA. Spray- dried lactose and process for preparing the same. United States Patent No. 4,802,926; 1989.

Vromans H, Bolhuis GK, Lerk CF, et al. Studies on the properties of lactose. VII. The effect of variations in primary particle size and percentage of amorphous lactose in spray-dried lactose. Int J Pharm 1987; 35(1–2): 29–37.

Elversson J, Millqvist-Fureby A, Alderborn G, Elofsson U. Droplet and particle size relationship and shell thickness of inhalable lactose particles during spray drying. J Pharm Sci 2003; 92(4): 900–910.

Harjunen PI, Lehto VP, Vaelisaari J, et al. Effects of ethanol to water ratio in feed solution on the crystallinity of spray dried lactose. Drug Dev Ind Pharm 2002; 28(8): 949–955.

Bhattachar SN, Hedden DB, Olsofsky AM, et al. Evaluation of the vibratory feeder method for assessment of powder flow properties. Int J Pharm 2004; 269: 385–392.

Corrigan DO, Healy AM, Corrigan OI. The effects of spray drying solutions of polyethylene glycol (PEG) and lactose/PEG on their physicochemical properties. Int J Pharm 2002; 235(1–2): 193–205.

Takeuchi H, Yasuji T, Yamamoto H, Kawashima Y. Spray dried lactose composite particles containing an ion complex of alginate–

chitosan for designing a dry coated tablet having a time controlled releasing function. Pharm Res 2000; 17: 94–99.

Kawashima Y, Serigano T, Hino T, et al. Effect of surface morphology of carrier lactose on dry powder inhalation property of pralukast hydrate. Int J Pharm 1998; 172: 179–188.

Harjunen P, Letho VP, Martimo K, et al. Lactose modifications enhance its drug performance in the novel multiple dose Taifun (R) DPI. Eur J Pharm Sci 2002; 16(4–5): 313–321.

Berggren J, Frenning G, Alderborn G. Compression behaviour and tablet-forming ability of spray-dried amorphous composite parti- cles. Eur J Pharm Sci 2004; 22: 191–200.

General References

Bolhuis GK, Chowhan ZT. Materials for direct compaction. In: Alderborn G, Nystro¨ m C, eds. Pharmaceutical Powder Compaction Technology. New York: Marcel Dekker, 1996: 473–476.

Borculo Domo Ingredients. Technical literature: Lactopress Spray- Dried, Lactopress Spray-Dried 250, 2003.

DMV International. Technical literature: Pharmatose DCL 11, Pharmatose DCL 14, 2004.

Fell JT, Newton JM. The characterization of the form of lactose in spray-dried lactose. Pharm Acta Helv 1970; 45: 520–522.

Fell JT, Newton JM. The production and properties of spray-dried lactose, part 1: the construction of an experimental spray drier and the production of spray-dried lactose under various conditions of operation. Pharm Acta Helv 1971; 46: 226–247.

Fell JT, Newton JM. The production and properties of spray-dried lactose, part 2: the physical properties of samples of spray-dried lactose produced on an experimental drier. Pharm Acta Helv 1971; 46: 425–430.

Fell JT, Newton JM. The production and properties of spray-dried lactose, part 3: the compaction properties of samples of spray-dried lactose produced on an experiemental drier. Pharm Acta Helv 1971; 46: 441–447.

Foremost Farms USA. Technical literature: NF Lactose-316 Fast Flo, 2004.

Meggle GmbH. Technical literature: Lactose excipients, 2004.

New Zealand Lactose. Technical literature: Super-Tab Spray-Dried, 2004.

Price R, Young PM. Visualisation of the crystallisation of lactose from the amorphous state. J Pharm Sci 2004; 93: 155–164.

Authors

S Edge, A Kibbe, K Kussendrager.

Date of Revision

5 August 2005.

Lanolin

Nonproprietary Names

BP: Wool fat

JP: Purified lanolin PhEur: Adeps lanae USP: Lanolin

Synonyms

Cera lanae; E913; lanolina; lanolin anhydrous; Protalan anhydrous; purified lanolin; refined wool fat.

Table I: Pharmacopeial specifications for lanolin.

Test JP 2001 PhEur 2005 USP 28

Identification + + —

Characters + + —

Melting range 37–438C 38–448C 38–448C Acidity and alkalinity + — +

Loss on drying 40.5% 40.5% 40.25%

Residue on ignition 40.1% — 40.1% Sulfated ash — 40.15% —

Chemical Name and CAS Registry Number

Anhydrous lanolin [8006-54-0]

Empirical Formula and Molecular Weight

The USP 28 describes lanolin as the purified wax-like substance obtained from the wool of the sheep, Ovis aries Linne´ (Fam. Bovidae), that has been cleaned, decolorized, and deodorized. It contains not more than 0.25% w/w of water and may contain up to 0.02% w/w of a suitable antioxidant; the PhEur 2005 specifies up to 200 ppm of butylated hydroxytoluene as an antioxidant.

See also Section 18.

Water-soluble acids and

alkalis

Water-soluble oxidizable substances

— + +

+ + +

Structural Formula

See Section 4.

Functional Category

Emulsifying agent; ointment base.

Applications in Pharmaceutical Formulation or Technology

Lanolin is widely used in topical pharmaceutical formulations and cosmetics.

Lanolin may be used as a hydrophobic vehicle and in the preparation of water-in-oil creams and ointments. When mixed with suitable vegetable oils or with soft paraffin, it produces emollient creams that penetrate the skin and hence facilitate the absorption of drugs. Lanolin mixes with about twice its own weight of water, without separation, to produce stable emulsions that do not readily become rancid on storage.

See also Section 18.

Description

Lanolin is a pale yellow-colored, unctuous, waxy substance with a faint, characteristic odor. Melted lanolin is a clear or almost clear, yellow liquid.

Pharmacopeial Specifications

See Table I.