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Lactose for Inhalation Excipient | Uses, Suppliers, and Specifications

Lactose for Inhalation is a speciality grade of lactose intended for use in dry inhalation devices as a carrier. It consists of Lactose monohydrate, Anhydrous lactose or a mixture of α-Lactose monohydrate and β-Lactose. It is supplied as a white or off-white crystalline powder of specified particle size. It is odourless.

Pharmacopoeial Compliance: Lactose for Inhalation conforms to the monograph “Lactose Monohydrate” in the USP-NF; Ph. Eur, and JP

Synonyms and Trade Names: Inhalation Lactose; Lactose for Inhalation; Lactohale®; Respitose®; Inhalac®

Uses and Applications: Carrier in Dry Powder Inhalers

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Aero Flo® 35 Monohydrate - KERRY

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Aero Flo® 25 Anhydrous - KERRY

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Respitose® ML001 - DFE Pharma

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Lactohale® 100 - DFE Pharma

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InhaLac® 70 - Meggle Pharma

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Description

Inhalation lactose is a unique inhalation grade lactose engineered with a narrow particle size distribution profile and unique shape and flow characteristics. It may be in the form of Lactose monohydrate (O-β-D-galactopyranosyl (1,4)-α-D-glucopyranose monohydrate), Anhydrous lactose (O-β-D-galactopyranosyl (1,4)-β-D-glucopyranose), or a mixture of the two (i.e O-β-D-galactopyranosyl (1,4)-β-D-glucopyranose and O-β-D-galactopyranosyl (1,4)-α-D-glucopyranose). Inhalation lactose occurs as white to off-white crystalline particles or powder, and is odourless and slightly sweet-tasting.

Lactose: Overview, Types and Key Properties

Lactose (IUPAC name of lactose is 4-O-(β-d-galactopyranosyl)-D-glucopyranose) is a naturally occurring disaccharide that consists of one molecule of β-D-galactose and one molecule of β-D-glucose molecules linked through a β1-4 glycosidic linkage. It is produced by the mammary epithelium of all lactating mammals. To date, milk is the only known significant source of lactose.

For pharmaceutical applications, Lactose is produced from whey as a by-product of the dairy industry. The process involves the crystallisation of a saturated whey concentrate. To minimise the risk of contamination from Bovine Spongiform Encephalopathy (BSE), additional refining and purification steps are undertaken, the result of which is a chemically pure excipient that carries no risks arising from being an animal-derived raw material.

Lactose exists naturally in the form of two isomers: α-Lactose (i.e β-D-galactopyranosyl-(1,4)-α-D-glucopyranose) and β-lactose (i.e β-D-galactopyranosyl-(1,4)-β-D-glucopyranose). The two forms have specific optical rotations [α]20D  of +89.4o and +35o, respectively, due to their differences in the spatial positioning of a H-atom and the -OH-group on C1 in the glucose moiety.

Conversion between the two anomers occurs via the open-chain form of the glucose moiety, and depending on the concentration and temperature, an equilibrium will establish at [α]20D  +55.3o, corresponding to ≈37% α-Lactose, and 63% β-Lactose. Changes in concentration or temperature can shift the equilibrium accordingly (for example, an increase in temperature or concentration increases levels of β-Lactose, and vice versa). Under typical conditions, however, Lactose in solution is considered to be a mixture of α-, and β-Lactose.

Crystal Forms of Lactose

Lactose crystallises from solution when its equilibrium solubility is exceeded (for instance, through the removal of water or a lowering of temperature). Various Lactose crystal forms can theoretically form. When Lactose is crystallised under standard processing conditions (typically <93.5 oC), the main crystalline form obtained is the α-Lactose monohydrate form, which is also the most stable form. In addition, α-Lactose monohydrate forms exist as hard and brittle ‘tomahawk-like’ crystals and is not hygroscopic. In the hydrated form, this form α-Lactose contains one mole of lactose and one mole of water. The water of hydration can be removed if the α-Lactose is heated to above 140 oC which produces anhydrous α-Lactose.

If the crystallisation is conducted at >93.5 oC, anhydrous β-lactose is obtained. This anomer forms small, kite-like brittle crystals that are brittle but also markedly more soluble. It exhibits minimal hygroscopicity, however, it is unstable, and will transform back to the α-Lactose form given the right conditions.

When a solution of Lactose is spray-dried, the rate of water removal is too rapid for crystallisation to occur. Instead, amorphous Lactose is produced which exists in a glassy state. This form also contains some water of hydration. Amorphous Lactose is hygroscopic and can adsorb water causing crystallisation into the α-Lactose monohydrate as a result of molecular mobility.

As a result of the differences in the physicochemical attributes of the different forms of lactose, grades of lactose exhibit differences in parameters such as melting point, density, and solubility, and ultimately, in their functionalities when it comes to their uses as pharmaceutical excipients.

Grades of Lactose for Inhalation

Lactose for Inhalation is manufactured from pharmaceutical-grade lactose by milling, sieving, air classifying, micronizing and/or blending select lots in dedicated facilities. Since there are several types of inhalation devices in existence (e.g reservoir devices, capsule devices and blister devices), they each place particular demands on lactose powder. For this reason, a number of lactose excipient grades are commercially available varying in terms of particle size distributions and other characteristics.

Chemical Structure & Identifiers


IUPAC Name O-β-D-galactopyranosyl-(1→4)-α-D-glucopyranose monohydrate
CAS Registration Number [5989-81-1]; [10039-26-6]; [64044-51-5]
Empirical Formula C12H22O11.H2O
Molecular weight 360.31
EC / EINECS Number 200-559-2
UNII Code (FDA) EWQ57Q8I5X

Regulatory Status

Inhalation lactose grades comply with α-Lactose monohydrate specification in the USP-NF, PhEur and JP. Inhalation grades require stricter microbial limits in order to satisfy the special requirements for dry powder inhaler formulations.

 

Physicochemical Properties

Physical form Solid, powder
Appearance White to off-white crystalline particles or powder
Bulk density 0.45 – 0.85g/cm3
Tapped density 0.75 – 0.85g/cm3
True density 1.545 g/cm3 for α-lactose monohydrate
Melting point 200.00205o C (typical) for anhydrous lactose.
Particle size distribution (d50) 1 – 120 µm
Water content ≤6.0%
BET Surface area (m2/g) 0.10 – 5.5
Solubility Soluble in water; sparingly soluble in ethanol

Pharmacopeoeal Specifications

Inhalation lactose grades comply with α-Lactose monohydrate specification in the USP-NF, PhEur and JP. Inhalation grades require stricter microbial limits in order to satisfy the special requirements for dry powder inhaler formulations.

Test USP-NF Ph.Eur
Official name Lactose monohydrate Lactose monohydrate
Authorised use Excipient specified
Definition specified specified
Identification A

B

C

A

B

C

D

Characters White or almost white crystalline powder White or almost white crystalline powder
Acidity of alkalinity specified specified
Clarity and colour of solution specified n/a
Appearance of solution n/a specified
Specific optical rotation 54.4o – 55.9o 54.4o – 55.9o
Absorbance

210-220nm

270-300nm

400nm

 

≤0.25

≤0.07

≤0.04

 

≤0.25

≤0.07

≤0.04

Heavy Metals ≤5 µg/g ≤5ppm
Water ≤4.5 – 5.5% ≤4.5 – 5.5%
Sulphated ash ≤0.1%
Microbial contamination

Aerobic bacteria

Fungi and yeast

Absence of E.coli & Salmonella

 

100cfu/g

50cfu/g

specified

 

100cfu/g

50cfu/g

specified

Protein and light-absorbing impurities specified n/a
Loss on drying ≤0.5% n/a
Assay  n/a n/a
Labelling specified n/a

Applications in Pharmaceutical Formulations or Technology

Lactose monohydrate is the excipient of choice for dry powder inhalers (DPI). It functions as a carrier and flow aid, playing an important role in the whole formulation process, from bulking the dose chamber in the dry powder device, to facilitating dose delivery through the action of the user. A number of scientific papers and opinions have been devoted to the specific role of lactose fines and discussion is still ongoing. It remains one of the few excipients accepted by all health authorities for use in inhaled formulations.

Several types of dry powder inhaler devices have been developed. They include reservoir devices, capsule devices and blister devices. Each design places specific requirements on powder characteristics. Thus, the properties of the Inhalation lactose grade are selected based on the different parameters, including the device type (flowability of the lactose), filling platform (flow of lactose), type of drug and how it is processed and the required drug release (fine lactose particles).

With reservoir devices, the dosing from the reservoir in the firing compartment is a key factor. In capsule or blister devices, the filling of the capsule or blister matters most. All these factors require different properties of the lactose powder. In a typical device, the lactose powder constitutes the largest proportion of formulation ingredients relative to the drug (which is typically in the order of 1-2%). In this case, the larger-sized excipient particles are responsible for the flow properties of the powder into the device.

The second consideration is the inhalation process. Here powder properties play again a major role, but the drug is designed to detach from the carrier. In this case, the interactions between excipient and drug are of critical importance. The very finely divided drug particles should be well mixed within the powder and adhere to the carrier in a way that permits the drug to be dislodged during inhalation but not whilst in the device.

For these reasons, the choice of type of lactose cannot be pointed out beforehand, and instead, each device and drug substance requires specific assessments to match them with a specific lactose grade.

Safety and Precautions

Lactose is widely used in oral pharmaceutical products and may also occasionally be used in intravenous injections. It has been used in pharmaceutical tablets for more than 100 years, thus its safety and toxicity are not in question. Furthermore, pharmaceutical grades of Lactose are required to achieve very high purity levels, including those standards required by the different monographs of the various pharmacopoeia.

Lactose has a clean sweet taste, without any aftertaste. The sweetness profile matches that of sucrose although its intensity is low due to the lower water solubility. Upon ingestion, Lactose is not actively absorbed by the intestine. For absorption to occur, the Lactose molecule needs to be hydrolysed into glucose and galactose. In vivo, the enzyme, lactase, produced by GI tract epithelial cells are responsible for splitting lactose.

In many mammals, the activity of lactase wanes shortly after weaning and then remains constant. However, in some individuals, the level of lactase is very low or non-existent. These individuals are not able to digest lactose (malabsorbers). Lactose that remains in the intestine undigested is transferred into the large intestine where it is fermented by gut flora to produce organic acids, such as lactic acid. This can cause additional symptoms linked to water retention, such as bloating, diarrhoea, and abdominal cramps. Although the majority of malabsorbers can handle lactose, there is a significant number that are intolerant, for whom the ingestion of even a small amount of lactose produces symptoms described above. For these individuals, avoidance of lactose is important.

Safety of Lactose in Diabetes

The complete limit on sugar in diets of diabetic patients is no longer the conventional approach. The aim of treatment is to achieve and maintain normal blood glucose levels. This can be accomplished by following a normal diet as long as energy intake is controlled and spread evenly throughout the day. For a diet consisting of between 150 and 250g of carbohydrates, the contribution to this by the amount of lactose ingested through tablets is insignificant. Thus, restrictions for diabetic patients to avoid lactose-containing medicines are not warranted.

Lactose and Cariogenicity

Lactose in its non-hydrolysed form is minimally cariogenic compared to sucrose. Streptococcus species that break down carbohydrates to produce organic acids responsible for enamel erosion are much less capable of digesting lactose compared with sucrose. Furthermore, since tablets and capsules are commonly swallowed with water, the rinsing effect leaves little residue for bacteria to work upon.

Transmissible Spongiform Encephalopathies

In the past, there base 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 TSF contamination; TSE risk is negligible if the calf rennet is produced in accordance with regulations.

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

Stability and Storage Conditions

Lactose is overall a highly stable excipient when stored under ambient conditions.  It is also relatively inert from a chemical point of view. The standard shelf life is 24-36 months. Lactose shows little tendency to react with formulation ingredients, including active ingredients. However, mould growth may occur under humid conditions (80% RH and above). For this reason, the raw materials should be stored correctly in accordance with recommended storage conditions of the manufacturer.

When handling Lactose, workers should observe established SHEQ protocols appropriate to the circumstances and quantity of material handled. Excessive generation of dust, or inhalation of dust, should be avoided.

Sustainability and Environmental Impact

Lactose is a natural disaccharide consisting of galactose and glucose and is present in the milk of most mammals. Commercially, it is produced from the whey of cows’ milk; whey being the residual liquid of the milk following cheese and casein production. Cows’ milk contains 4.4 – 5.2% lactose; while lactose constitutes 38% of the total solid comment of milk. A naturally-derived substance, lactose is an inert and non-toxic excipient and considered safe for the environment, with minimal long-term impact on ecology or marine life. However, while the dairy industry has faced questions about its long-term sustainability, lactose is a secondary product of the dairy sector and therefore represents a net realisable value. Lactose Monohydrate excipient grade achieved a total score of 72/100 by the Excipients Forum Sustainable Chemistry™ score.

Manufacturers & Suppliers

Kerry Group (Sheffield Biosciences)

  • Aero Flor® 35 Monohydrate
  • Aero Flor® 55 Monohydrate
  • Aero Flor® 60S Monohydrate
  • Aero Flor® 65 Monohydrate
  • Aero Flor® 25 Anhydrous
  • Aero Flor® 85 Anhydrous

DFE Pharma GmbH & Co. KG.

  • Respitose® ML001
  • Respitose® ML003
  • Respitose® SV001
  • Respitose® SV010
  • Respitose® SV014
  • Lactohale® 100
  • Lactohale® 200
  • Lactohale® 201
  • Lactohale® 206
  • Lactohale® 220
  • Lactohale® 300

Meggle Pharma

  • InhaLac® 70
  • InhaLac® 120
  • InhaLac® 160
  • InhaLac® 230
  • InhaLac® 251

Additional Resources (Downloads)

References and Literature Used

[1] Y. Kawashima, T. Serigano, T. Hino, H. Yamamoto, H. Takeuchi, Effect of surface morphology of carrier lactose on dry powder inhalation property of pranlukast hydrate, International Journal of Pharmaceutics, 172 (1998) 179-188.

[2] P.M. Young, S. Edge, D. Traini, M.D. Jones, R. Price, D. El-Sabawi, C. Urry, C. Smith, The influence of dose on the performance of dry powder inhalation systems, International Journal of Pharmaceutics, 296 (2005) 26-33.

[3] C.P. Watling, J.A. Elliott, R.E. Cameron, Entrainment of lactose inhalation powders: A study using laser diffraction, European Journal of Pharmaceutical Sciences, 40 (2010) 352-358.

[4] X. Kou, L.W. Chan, H. Steckel, P.W.S. Heng, Physico-chemical aspects of lactose for inhalation, Advanced Drug Delivery Reviews, 64 (2012) 220-232.

[5] F. Grasmeijer, A.J. Lexmond, M.v.d. Noort, P. Hagedoorn, A.J. Hickey, H.W. Frijlink, A.H.d. Boer, New Mechanisms to Explain the Effects of Added Lactose Fines on the Dispersion Performance of Adhesive Mixtures for Inhalation, PLoS One, 9 (2014).

[6] A.M. Healy, M.I. Amaro, K.J. Paluch, L. Tajber, Dry powders for oral inhalation free of lactose carrier particles, Advanced Drug Delivery Deviews, 75 (2014) 32-52.

[7] Y. Rahimpour, M. Kouhsoltani, H. Hamishehkar, Alternative carriers in dry powder inhaler formulations, Drug Discovery Today, 19 (2014) 618-626.

[8] J. Robles, L. Motheral, Hypersensitivity reaction after inhalation of a lactose-containing dry powder inhaler, the Journal of Pediatric Pharmacology and Therapeutics, 19 (2014) 206-211.

[9] N. Wauthoz, I. Hennia, S. Ecenarro, K. Amighi, Impact of capsule type on aerodynamic performance of inhalation products: A case study using a formoterol-lactose binary or ternary blend, International Journal of Pharmaceutics, 553 (2018) 47-56.

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