Tuesday, May 12, 2009

Osmotic Drug Delivery

For many decades treatment of an acute disease or a chronic illness has been mostly accomplished by delivery of drugs to patients using various pharmaceutical dosage forms. Traditionally, the oral drug delivery has been popular as the most widely utilized route of administration among all the routes that have been explored for the systemic delivery of drugs. Conventional oral drug delivery systems are known to provide an immediate release of drug, in which one cannot control the release of the drug and effective concentration at the target site. The bioavailability of drug from these formulations may vary significantly, depending on factors such as physico-chemical properties of the drug, presence of excipients, various physiological factors such as the presence or absence of food, pH of the GI tract, GI motility, etc.1 To overcome this limitation of oral route is replied by parenteral route. This route offers the advantage of reduced dose, targeting of site and avoiding GI stability, hepatic by-pass of drug molecule.

In the recent years, pharmaceutical research has led to the development of several novel drug delivery systems. The role of drug development is to take a therapeutically effective molecule with sub-optimal physicochemical and/or physiological properties and develop an optimized product that will still be therapeutically effective but with additional benefits such as2

* Sustained and consistent blood levels within the therapeutic window
* Enhanced bioavailability
* Reduced interpatient variability
* Customized delivery profiles
* Decreased dosing frequency
* Improved patient compliance
* Reduced side effects

The drug release can be modulated by different ways but the most of novel drug delivery systems are prepared using matrix, reservoir or osmotic principle. In matrix systems, the drug is embedded in a polymer matrix and the release takes place by partitioning of drug into the polymer matrix and the surrounding medium. In contrast, reservoir systems have a drug core surrounded by a rate controlling membrane. The osmotic systems utilize the principles of osmotic pressure for the delivery of drugs in both the routes oral as well as parenteral.3
1.1 Osmosis

Osmosis can be defined as the net movement of water across a selectively permeable membrane driven by a difference in osmotic pressure across the membrane. It is driven by a difference in solute concentrations across the membrane that allows passage of water, but rejects most solute molecules or ions. Osmotic pressure is the pressure which, if applied to the more concentrated solution, would prevent transport of water across the semipermeable membrane.

The first osmotic effect was reported by Abbe Nollet in 1748. Later in 1877, Pfeffer performed an experiment using semi-permeable membrane to separate sugar solution from pure water. He showed that the osmotic pressure of the sugar solution is directly proportional to the solution concentration and the absolute temperature. In 1886, Vant Hoff identified an underlying proportionality between osmotic pressure, concentration and temperature. He revealed that osmotic pressure is proportional to concentration and temperature and the relationship can be described by following equation.

Π = Ø c RT

Where, p = Osmotic pressure

Π = osmotic coefficient

c = molar concentration

R = gas constant

T = Absolute temperature

Osmotic pressure is a colligative property, which depends on concentration of solute that contributes to osmotic pressure. Solutions of different concentrations having the same solute and solvent system exhibit an osmotic pressure proportional to their concentrations. Thus a constant osmotic pressure, and thereby a constant influx of water can be achieved by an osmotic delivery system that results in a constant zero order release rate of drug.4
1.2 Osmotically controlled drug delivery systems

Osmotic pressure is used as driving force for these systems to release the drug in controlled manner. Osmotic drug delivery technique is the most interesting and widely acceptable among all other technologies used for the same. Intensive research has been carried out on osmotic systems and several patents are also published. Development of osmotic drug delivery systems was pioneered by Alza and it holds major number of the patents analyzed and also markets several products based on osmotic principle. These systems can be used for both route of administration i.e. oral and parenterals. Oral osmotic systems are known as gastro-intestinal therapeutic systems (GITS). Parenteral osmotic drug delivery includes implantable pumps.

Historical aspects of osmotic pumps

About 75 years after discovery of the osmosis principle, it was first used in the design of drug delivery systems.5 Rose and Nelson, the Australian scientists, were initiators of osmotic drug delivery. In 1955, they developed an implantable pump, which consisted of three chambers: a drug chamber, a salt chamber contains excess solid salt, and a water chamber. The drug and water chambers are separated by rigid semipermeable membrane. The difference in osmotic pressure across the membrane moves water from the water chamber into the salt chamber. The volume of the salt chamber increases because of this water flow, which distends the latex diaphragm separating the salt and drug chambers, thereby pumping drug out of the device. The design and mechanism of this pump is comparable to modern push-pull osmotic pump. The major disadvantage of this pump was the water chamber, which must be charged before use of the pump. The pumping rate of this push-pull pump is given by the equation.

dM/dt = dV/dt x c

In general, this equation, with or without some modifications, applies to all other type of osmotic systems.

Several simplifications in Rose-Nelson pump were made by Alza Corporation in early 1970s. The Higuchi-Leeper pump is modified version of Rose-Nelson pump. It has no water chamber, and the device is activated by water imbibed from the surrounding environment. The pump is activated when it is swallowed or implanted in the body. This pump consists of a rigid housing, and the semipermeable membrane is supported on a perforated frame. It has a salt chamber containing a fluid solution with excess solid salt. Recent modification in Higuchi-Leeper pump accommodated pulsatile drug delivery. The pulsatile release was achieved by the production of a critical pressure at which the delivery orifice opens and releases the drug.6

Higuchi-Leeper pump

Fig. 1: Higuchi-Leeper pump

Further simplified variant of Rose-Nelson pump was developed by Higuchi and Theeuwes. This pump comprises a rigid, rate controlling outer semipermeable membrane surrounding a solid layer of salt coated on the inside by an elastic diaphragm and on the outside by the membrane. In use, water is osmotically drawn by the salt chamber, forcing drug from the drug chamber.7

Higuchi-Theeuwes pump

Fig. 2: Higuchi-Theeuwes pump

In 1975, the major leap in osmotic delivery occurred as the elementary osmotic pump for oral delivery of drugs was introduced. The pump consists of an osmotic core containing the drug, surrounded by a semipermeable membrane with a delivery orifice. When this pump is exposed to water, the core imbibes water osmotically at a controlled rate, determined by the membrane permeability to water and by the osmotic pressure of the core formulation. As the membrane is non-expandable, the increase in volume caused by the imbibition of water leads to the development of hydrostatic pressure inside the tablet. This pressure is relieved by the flow of saturated solution out of the device through the delivery orifice. This process continues at a constant rate until the entire solid agent inside the tablet has been dissolved and only a solution filled coating membrane is left. This residual dissolved agent continues to be delivered at a declining rate until the osmotic pressure inside and outside the tablet are equal. Normally, the EOP delivers 60-80% of its contents at a constant rate, and there is a short lag time of 30-60 min as the system hydrates before zero order delivery from the EOP is obtained.8

Apart from oral osmotic pumps, the development of miniature implantable osmotic pumps in the mid-1970s was a major breakthrough to deliver wide range of drugs and hormones, including peptides at constant and programmed rate in mice, rat and larger animals. These implants provide a convective stream of drug solution that can be directed through suitable catheter connections to sites in the animal remote from itself.9 Most recently the implantable pumps for human use are developed to delivery the drug for targeting or systemic application.
2.0 Classification of Osmotic drug delivery systems:

Many forms of osmotic pumps are reported in the literature but, in general they can be divided in oral and implantable systems. The detailed information on various osmotic systems is classified in Table 1.
2.1 Oral osmotic drug delivery systems

As oral route is the most popular route of administration, most of the osmotic systems are developed as oral drug delivery. It is possible to deliver APIs at zero-order release rate, independent of gastric pH and hydrodynamic conditions with these osmotically controlled drug delivery systems.

These systems can be further classified in

* Single chamber osmotic system: Elementary osmotic pump
* Multi-chamber osmotic systems:
o Tablets with second expandable osmotic chamber: push-pull osmotic pump
o Tablets with second non-expandable osmotic chamber: Two systems falls in this class i.e. 1) Drug solution gets diluted in the second chamber before leaving device and 2) Two separate EOP tablet formed in a single tablet

* Miscellaneous: Controlled porosity osmotic pumps, multiparticulate osmotic pump10, osmotic bursting osmotic pump11, Effervescent activity-based osmotic systems12, Lipid osmotic pump13

2.2 Implantable osmotic drug delivery systems
2.2.1 For human use:

More recently, osmotic principles have been applied to human parenteral therapy, resulting in the development of the DUROS® technology. These technologies allow drug delivery for site-specific as well as systemic use for delivery periods of days to 1 year.14

All materials in the DUROS system were chosen for their biocompatibility and suitability for implant use. The drug-contacting materials are also screened for compatibility with the drug and the specific drug formulation excipients. Radiation sterilization (gamma) may be utilized to sterilize the final drug product. If the drug formulation cannot withstand sterilizing doses of radiation, then a DUROS subassembly is radiation sterilized, and the drug formulation is added in a final aseptic operation. Hence, the materials in the DUROS system were also screened for their ability to withstand sterilizing doses of radiation.

applications, the preferred site of implantation is subcutaneous placement in the inside of the upper arm. When implanted, a large, constant osmotic gradient is established between the tissue water and the osmotic engine. The engine is specifically formulated with an excess of NaCl, such that solid NaCl is present throughout the delivery period. This results in a constant osmotic gradient throughout the delivery period. In response to the osmotic gradient, water is drawn across the membrane into the osmotic engine.
Compounds delivered using DUROS® Technology

DUROS® has the potential to provide more flexibility than competitive products regarding the types of drugs that can be administered, including proteins, peptides and genes because the drug dispensing mechanism is independent from the drug substance.
2.2.2 For animal models:

ALZET osmotic pumps are miniature, implantable pumps used for research in mice, rats, and other laboratory animals. These infusion pumps continuously deliver drugs, hormones, and other test agents at controlled rates from one day to six weeks without the need for external connections or frequent handling. Their unattended operation eliminates the need for repeated nighttime or weekend dosing.15

ALZET pumps operate by osmotic displacement. An empty reservoir within the core of the pump is filled with the drug or hormone solution to be delivered. Due to the presence of a high concentration of salt in a chamber surrounding the reservoir (but isolated from it by an impermeable layer), water enters the pump through its outer surface (a semipermeable layer). The entry of water increases the volume in the salt chamber, causing compression of the flexible reservoir and delivery of the drug solution into the animal via the exit port.

ALZET pumps can be used for systemic administration when implanted subcutaneously or intraperitoneally. They can be attached to a catheter for intravenous, intracerebral, or intra-arterial infusion. ALZET pumps can also be used for targeted delivery, where the effects of a drug or test agent are localized in a particular tissue or organ, by means of a catheter. The pumps have been used to target delivery to a wide variety of sites including the spinal cord, spleen, liver, organ or tissue transplants, and wound healing sites.

ALZET pumps have been used successfully to deliver hundreds of different compounds, including antibodies, chemotherapeutic drugs, cytokines, growth factors, hormones, and peptides.

Table 1: Different types of osmotic systems-Design, mechanism and uses

Osmotic System

Design of Dosage Form




Oral osmotic tablets

Single chamber osmotic pumps

+Elementary Osmotic Pump (EOP)8, 16

Core: API ± osmogents

Coat: Semi permeable membrane with delivery orifice

The water penetrates inside the dosage form at the rate determined by the fluid permeability of the membrane and osmotic pressure of core formulation. This will result in formation of saturated solution of drug within the core, which is dispensed at a controlled rate from the delivery orifice in the membrane.

· Moderately soluble API

· 60-80% constant release


Controlled-porosity osmotic pump (CPOP)17, 18

Core: API ± osmogents

Coat: Semi permeable membrane with water soluble additives

Water-soluble additives dissolve after coming in contact with water, resulting in an in situ formation of a microporous membrane. The resulting membrane is substantially permeable to both water and dissolved solutes and the mechanism of drug release was found to be osmotic.


Osmotic bursting osmotic pump19

Core: API ± osmogents

Coat: Semi permeable membrane without delivery orifice

When placed in aqueous environment, water is imbibed and hydraulic pressure is built up inside the system, then wall ruptures and the contents are released.

· For pulsated release

Multi-chamber osmotic pumps

Push-pull osmotic pump (PPOP)20 , 21

Core Tablet:

Layer 1: API ± osmogents

Layer 2: Polymeric osmotic agents

Coat: Semi permeable membrane with delivery orifice

After coming in contact with the aqueous environment, polymeric osmotic layer swells and pushes the drug layer, and thus releasing drug in the form of fine dispersion via the orifice.

· For delivery of APIs having extremes of water solubility

· Modifications can be done:

- delayed push-pull

- multi-layer push-pull

- push-stick system


Sandwiched Osmotic tablets (SOTS)22

Core tablet: 3 layers

Middle layer: push layer

2 attached layers: API

Coat: Semi permeable membrane with two side delivery orifice

The middle push layer swells and drug is released from delivery orifices.

· API release from two sides of tablets.


Oral osmotic capsules


Single osmotic unit or a unit containing as many as five to six PPOP filled in hard gelatin capsule. The osmotic system is enteric coated.

Gelatin capsule shell dissolves after coming in contact with GI fluids. Enteric coating on the system prevents entry of fluid from stomach to the system and it dissolves after entering into intestine. The water imbibes into the core and push compartment will swell. At the same time, the flowable gel is formed which is pushed out via delivery orifice at predetermined rate.

· For colon-targeting and can be used as local or systemic therapy.


L-OROS (Soft-Cap & Hard-Cap)24, 25

Liquid API formulation is present in a soft gelatin capsule, which is surrounded with the barrier layer, the osmotic layer, and the release rate-controlling membrane. A delivery orifice is formed through these three layers.

When the system comes in contact with aqueous environment, water permeates across the rate controlling membrane and activates the osmotic layer. The expansion of the osmotic layer results in the development of hydrostatic pressure inside the system, thereby forcing the liquid formulation to break through the hydrated gelatin capsule shell at the delivery orifice.

· To deliver APIs as liquid formulations and combine the benefits of extended release with high bioavailability.

· Suitable for controlled delivery of lipophilic APIs


Pelleted delayed release26

Multi-particulate delayed release systems consist of pellets of API (with or without osmogents) coated with SPM.

Rapid expansion of membrane after coming in contact with aqueous environment resulting in pore-formation and API release

· High flux rates and thus having higher release rates for poorly water-soluble APIs

Asymmetric membrane capsule27

Capsule wall made up of water insoluble semipermeable polymer

Imbibition of water through the capsule wall and dissolving soluble components within it and releasing from same wall

· High water permeability and controlled porosity

Telescopic capsule for delayed release28, 29

This device consists of two chambers, the first contains the drug and an exit port, and the second contains osmotic engine. Layer of wax-like material separates the two sections.

As fluid is imbibed the housing of the dispensing device, the osmotic engine expand and exerts pressure on the slidable connected first and second wall sections.


Implantable osmotic systems

Duros osmotic pump30

Implantable drug-dispensing osmotic pump, shaped as a small rod with titanium housing.

Through osmosis, water from the body is slowly drawn through the semi-permeable membrane into the pump by osmotic agent residing in the engine compartment, which expands the osmotic agent and displaces a piston to dispense small amounts of drug formulation from the drug reservoir through the orifice

· Systemic or site-specific administration of a drug


Alzet osmotic pumps15

Empty reservoir within the core of the pump is filled with the drug or hormone solution to be delivered and is surrounded by salt chamber with impermeable layer between them.

Water enters into the salt chamber through semipermeable membrane and causes compression of flexible reservoir and delivery of drug solution.

· To deliver drugs, hormones, and other test agents continuously at controlled rates from one day to six weeks


3.0 General mechanism for drug release from osmotic pumps

As described earlier, the basic equation which applies to osmotic systems is

dM / dt = dV / dt x c


dM / dt= mass release

dV / dt= volumetric pumping rate

c = concentration of drug


dV / dt = (A/ h)Lp ( σ ΔΠ -Δp)


A= membrane area

h= thickness of membrane

Lp= mechanical permeability

σ =reflection coefficient

ΔΠ=osmotic pressure difference

Δp = hydrostatic pressure difference

As the size of orifice delivery increases, Δp decrease, so ΔΠ >> Δp and equation becomes

dV / dt = A/ h Lp (σ ΔΠ )

When the osmotic pressure of the formulation is large compared to the osmotic pressure of the environment, p can be substituted for Dp.

dV / dt = A / h Lp σΠ = A / hk Π (k = Lpσ = membrane permeability)

Now, equation (1) can be given as

dM / dt = (A / h) k Π c = (A / h) k Π S (S = solubility of drug, c taken as S)
4.0 Factors affecting drug release rate
4.1 Solubility:

APIs for osmotic delivery should have water solubility in the desired range to get optimize drug release. However, by modulating the solubility of these drugs within the core, effective release patterns may be obtained for the drugs, which might otherwise appear to be poor candidate for osmotic delivery.

Solubility-modifying approaches:

* Use of swellable polymers31: vinyl acetate copolymer, polyethylene oxide have uniform swelling rate which causes drug release at constant rate.
* Use of wicking agents: These agents may enhance the surface area of drug with the incoming aqueous fluids. e.g. colloidal silicon dioxide, sodium lauryl sulfate, etc. Ensotrol® technology uses the same principle to deliver drugs via osmotic mechanism.
* Use of effervescent mixtures32: Mixture of citric acid and sodium bicarbonate which creates pressures in the osmotic system and ultimately controls the release rate.
* Use of cyclodextrin derivatives33: They are known to increase solubility of poorly soluble drugs. The same phenomenon can also be used for the osmotic systems.
* Use of alternative salt form: Change in salt form of may change solubility.
* Use of encapsulated excipients34: Solubility modifier excipient used in form of mini-tablet coated with rate controlling membrane.
* Resin Modulation approach35: Ion-exchange resin methods are commonly used to modify the solubility of APIs. Some of the resins used in osmotic systems are Poly (4-vinyl pyridine), Pentaerythritol, citric and adipic acids.
* Use of crystal habit modifiers: Different crystal form of the drug may have different solubility, so the excipient which may change crystal habit of the drug can be used to modulate solubility.36
* Co-compression of drug with excipients 37,38: Different excipients can be used to modulate the solubility of APIs with different mechanisms like saturation solubility, pH dependent solubility. Examples of such excipients are organic acids, buffering agent, etc.

4.2 Osmotic pressure:

The next release-controlling factor that must be optimized is the osmotic pressure gradient between inside the compartment and the external environment.

The simplest and most predictable way to achieve a constant osmotic pressure is to maintain a saturated solution of osmotic agent in the compartment. The following table shows osmotic pressure of commonly used solutes in CR formulations39.

Table 2

4.3 Size of delivery orifice:

To achieve an optimal zero order delivery profile, the cross sectional area of the orifice must be smaller than a maximum size to minimize drug delivery by diffusion through the orifice. Furthermore, the area must be sufficiently large, above a minimum size to minimize hydrostatic pressure build up in the system. The typical orifice size in osmotic pumps ranges from 600µ to 1 mm.

Methods to create a delivery orifice in the osmotic tablet coating are:

* Mechanical drill
* Laser drill: This technology is well established for producing sub-millimeter size hole in tablets. Normally, CO2 laser beam (with output wavelength of 10.6µ) is used for drilling purpose, which offers excellent reliability characteristics at low costs.40, 41
* Indentation that is not covered during the coating process42: Indentation is made in core tablets by using modified punches having needle on upper punch. This indentation is not covered during coating process which acts as a path for drug release in osmotic system.
* Use of leachable substances in the semipermeable coating : e.g. controlled porosity osmotic pump

5.0 Basic components of Osmotic systems
5.1 Drug:

which have short biological half-life and which is used for prolonged treatment are ideal candidate for osmotic systems. Various drug candidates such as Diltiazem HCl43, Carbamazepine, Metoprolol44, Oxprenolol, Nifedipine45, Glipizide46, etc are formulated as osmotic delivery.
5.2 Osmotic agent:

Osmotic components usually are ionic compounds consisting of either inorganic salts or hydrophilic polymers. Some of the osmotic agents that can be used for such systems are classified below. Different type of osmogents can be used for such systems are categorized as water-soluble salts of inorganic acids like magnesium chloride or sulfate; lithium, sodium, or potassium chloride; sodium or potassium hydrogen phosphate; water-soluble salts of organic acids like sodium and potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, sodium ascorbate; Carbohydrates like mannose, sucrose, maltose lactose; water-soluble amino acids and organic polymeric osmogents, etc.
5.3 Semipermeable membrane:

An important part of the osmotic drug delivery system is the SPM housing. Therefore, the polymeric membrane selection is key to osmotic delivery formulation. The membrane must possess certain performance criteria such as:

* Sufficient wet strength and water permeability
* Should be biocompatible
* Rigid and non-swelling
* Should be sufficient thick to withstand the pressure within the device.

Any polymer that is permeable to water but impermeable to solute can be used as a coating material in osmotic devices. e.g. Cellulose esters like cellulose acetate, cellulose acetate butyrate, cellulose triacetate and ethyl cellulose and Eudragits. 47
5.4 Plasticizers:

Different types and amount of plasticizers used in coating membrane also have a significant importance in the formulation of osmotic systems. They can change visco-elastic behavior of polymers and these changes may affect the permeability of the polymeric films. Some of the plasticizers used are as below:

* Polyethylene glycols
* Ethylene glycol monoacetate; and diacetate- for low permeability
* Tri ethyl citrate
* Diethyl tartarate or Diacetin- for more permeable films

6.0 Advantages of osmotic drug delivery systems

Osmotic drug delivery systems for oral and parenterals use offer distinct and practical advantages over other means of delivery. The following advantages have contributed to the popularity of osmotic drug delivery systems.48

* The delivery rate of zero-order is achievable with osmotic systems.
* Delivery may be delayed or pulsed, if desired.
* Higher release rates are possible with osmotic systems compared with conventional diffusion-controlled drug delivery systems.
* The release rate of osmotic systems is highly predictable and can be programmed by modulating the release control parameters.
* For oral osmotic systems, drug release is independent of gastric pH and hydrodynamic conditions.
* The release from osmotic systems is minimally affected by the presence of food in gastrointestinal tract.
* A high degree of in vivo- in vitro correlation (IVIVC) is obtained in osmotic systems.

7.0 Marketed products

Elementary osmotic pump

Brand Name


Efidac 24®


Acutrim ®


Sudafed 24®


Volmax ®


Minipress XL®


Push-pull osmotic systems

Ditropan XL ®

Oxybutynin chloride

Procardia XL®


Glucotrol ®


Covera HS ®

Verapamil HCl

DynaCirc CR®




Implantable osmotic systems


Leuprolide acetate


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