NOVEL DRUG DELIVERY SYSTEMS

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Novel drug delivery systems

NOVEL DRUG DELIVERY SYSTEMS

I. INTRODUCTION

Drug delivery constitutes one of the major components in the drug development process, in addition to the assurance that the medication is effective and free of serious side effects.

Drug delivery via intravenous, intramuscular, subcutaneous, and peritoneal administration requires training, supervision, and possibly skilled personnel.

New and promising drug delivery systems have been created and modified to ensure that drugs are delivered to the appropriate targets of action in the body without major complications.

II. ORAL DRUG DELIVERY

The potential sites for absorption of drugs in the gastrointestinal tract are the buccal cavity, stomach, small and large intestines, and rectum.

The small intestine is a common area for drug absorption. Once absorbed by the gastrointestinal tract, a drug is channelled through the portal vein to the liver before gaining access to the systemic circulation for delivery to its site of action. T

he presence of degradative enzymes along the gastrointestinal tract and the acidic environment in the stomach constitute some of the barriers for delivery of drugs from the oral cavity.

Low oral bioavailability of a drug is usually caused by relative insolubility in water, poor intestinal permeability, or biodegradation in the upper portion of the digestive tract.

Because the liver is another major site of biotransformation of drugs, the bioavailability of some drugs may not be as high as expected.

Administration of a prodrug that makes use of the biotransformation process in the intestine and liver can greatly enhance the availability of the drug at the site of action.

A high proportion of drug administered in the rectum is absorbed and drained into the venous circulation, thereby bypassing the initial biotransformation step.

Unless modified in some way, drugs such as hormones, proteins, small peptides, and some antibiotics are not suitable for this route of administration.

One way to deliver drugs into the gastrointestinal tract is in the form of a remote drug delivery capsule, which is a nondisintegrating remote control device with a volume less than 1 mL.

The capsule is made up of outer and inner sleeves with a series of predrilled open slots. The slots are not aligned following introduction of the drug inside the capsule.

The capsule is then swallowed by the patient.

Classification of Beta Lactam Antibiotics

At the appropriate time, a remote electronic signal will cause the series of slots in the inner and outer sleeves of the capsule to align and release the drug.

With the use of indium-111 and technetium-99m, the transit of the capsule through the gastrointestinal tract was followed with gamma scintigraphy in human volunteers to determine its capability of drug release at designated sites.

Because of its relative large dimensions (35 mm ×10 mm), the capsule took a slightly longer time (approximately 1.5 h) to be cleared from the stomach than that of other nondisintegrating systems.

The times for the capsule to reach the small and the large intestines were also noted. About 30 h were needed to traverse the gastrointestinal tract in a human volunteer.

The contents of the capsules were successfully released by electronic stimuli when they reached the intended site either in the stomach, early small bowel, distal small bowel, or colon.

A. Stomach

Helicobacter pylori has been demonstrated to be the cause of gastric ulcers. It has been constituted that a localized dose of tetracycline and also metronidazole in the abdomen is necessary for the destruction of the bacteria.

The situation for the treatment of this condition is to arrangement of a system that constantly delivers antibiotics with elongated gastric retention time.

A hydrophilic 3 layered asymmetric configuration delivery method containing metronidazole, tetracycline, and bismuth with a floating characteristic was generated for this intention.

The leading excipients were sodium bicarbonate NaCO3, polyethylene oxide, and lactose.

On introduction of the 3 layer drug system to dissolution medium, bismuth was discharged instantly, while the liberation of tetracycline and metronidazole precede zero-order (0) kinetics over a period of 5 hours to 7 hours.

The system also display 30 minutes after sinking in the dissolution medium and rest floating until all the antibiotics were discharged. The floating characteristic is especially essential in that it delays gastric emptying.

B. Colon

Some disorder inflammatory diseases, e.g., Crohn’s disease, possess focal, often transmural, injury in the small intestine and/or colon with excess intestinal manifestations.

For the handling of these diseases, it may be essential to deliver dosage forms that release drugs only inside the colon and without failure in the upper gastrointestinal tract.

One way is to prepare water insoluble polymers that are stable in the stomach and small intestine, but degrade in the reductive environment of the large intestines.

Representative polymers can be prepared by reaction of an α, ω-diaminopolyether with a di N-oxysuccinimidylester of 3,3 -dithiodipropionic acid.

The polymer is used to coat drug-containing pellets, e.g., Eudragit E100. When the polymer is degraded in the large intestine, the drug is released.

On administration to human volunteers, it was found that the time for the initial degradation of the polymer from the drug-containing pellets ranged from 7.7 to 10.1 h and occurred in the proximal and transverse colon.

It was also noted that the time required for drug from the colon-specific delivery system to reach its destination was greatly slowed by the presence of food in the gastrointestinal tract.

Time-lapse sequential stratigraphic imaging over 24 h in human volunteers showed that polymer disintegration and hence drug release would not occur until approximately 5 h after gastric emptying in fasted or fed subjects.

Another colon-specific delivery system consists of core beads made up of microcrystalline cellulose, Carbopol, and a drug.

These beads are coated sequentially with a controlled-release film of Eudragit RS30D or Aqua coat and an enteric film of Eudragit L30D.

Carbopol is a binder, which is sensitive to pH and swells in the higher pH region of the intestine and colon.

The swelling ruptures the film coating, resulting in the release of the drug.

A dissolution test indicated that there was slow release of the drug at pH values less than 6.5, but the release at pH greater than 6.5 was rapid.

III. DIRECT DRUG DELIVERY

The nasal cavity and the rectum are unique sites of drug delivery in that the drugs will be absorbed directly into the bloodstream. These routes have been explored for possible use.

A. Nasal Route

Ondansetron (OND), a 5-hydroxytryptamine3 receptor antagonist, has been used for prevention of nausea and vomiting associated with emetogenic cancer therapy.

In view of the condition being treated, intravenous and oral dosage forms of OND may be inconvenient and/or unfeasible for specific patient populations.

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A dose of 1 mg/kg OND (Zofran injection, 2 mg/mL) was administered to male Sprague– Dawley rats intravenously or intra nasally.

The nasal administration route of OND was superior to the oral route (in humans, the oral absolute bioavailability is only 56% and the time to peak concentration is 1.0–2.1 h) and as effective as the intravenous route.

Cystic fibrosis is a hereditary disorder caused by mutation in the cystic fibrosis transmembrane conductance regulator gene that encodes a cyclic adenosine monophosphate regulated chloride channel.

Defects in chloride ion diffusion in the airway epithelial lead to irregular airway secretions, diminished mucocillary clearance, chronic bacterial pathologic process, bronchiectasis, and premature death.

Delivery of the cystic fibrosis transmembrane conductance regulator cDNA by adenovirus vectors or the plasmid–liposome complex resulted in transient correction of the defects in patients with cystic fibrosis.

B. Rectum

For drugs that have pathetic oral bioavailability, rectal administration of pro drugs can alteration of their absorption.

For E.g., nalbuphine is a painkiller with potency close to 0.5–0.9 that of morphine.

It is used for the relief of moderate to severe pain from a variety of causes, e.g., surgery, trauma, cancer, kidney, or biliary colic pain.

IV. DERMATOLOGICAL DELIVERY SYSTEM

The skin represent a tempting area for the delivery of drugs. However, due to its function as a barrier to unwelcome external influence, the skin presents a formidable challenge to researchers for drug delivery.

Experiments were performed to increase drug penetration into the skin by the application of short, high-voltage (100 V) pulses, ultrasound, and iontophoresis.

All these procedures were able to increase permeability parameters, e.g., lag time, permeability coefficient, skin content of drug, and 24-h receptor concentration, in isolated skin samples from hairless mice or human cadavers.

In addition, enhancers such as terpenes, 1-dodecyl hexahydro-2H-azepine-2-one, N-dodecyl-2-pyrrolidinone, glycyrrhizin (from Chinese herbal medicine), and ethosomes, were tested to increase transdermal delivery of drugs.

Ethosomes, phospholipid vesicles of short-chain alcohols, were shown to deliver model drug molecules, e.g., testosterone, to a skin depth of 240 μ, compared with the delivery of testosterone to a depth of 20μ by liposomes.

Ethosomes also have a high entrapment capacity so that more drug can be delivered. Transdermal delivery of proteins, oligonucleotides, and DNA is severely limited because of their size.

Microfabricated microneedles can be used to deliver these highly impermeable compounds across the skin.

Microfabrication techniques including deep reactive etching, micromolding, and electroplating were used to generate arrays of hollow silicon and metal needles.

These microneedles were shown to penetrate the stratum corneum of the skin without breaking and without stimulation of nerves in the deeper tissues.

The volume of water delivered by the microneedles was similar to that of a 26-gauge needle.

In vitro transport experiments using heat-stripped human epidermis mounted in Franz diffusion chambers showed that insertion of hollow silicon microneedles resulted in skin permeabilities to calcein, insulin, and bovine serum albumin on the order of 10−1 cm/h.

In addition, in vivo experiments showed that insulin (Humulin) delivered by microneedles to hairless rats caused large reductions in blood glucose levels.

V. TUMOR TARGETED DRUG DELIVERY SYSTEMS

Cancers are cancerous tumours produced by an ungoverned and unregulated growth potential. These tumours are able to grow locally by penetration of surrounding tissues and systematically by metastasis to extreme sites.

The occurrence of cancer cells could be due either to imperfection in the mechanisms accountable for regulating cell development or terminal differentiation.

Solid tumours shows a reductive environment because of hypoxia and the high production of bio reductive enzymes.

To take benefit of the characteristics of the environment supply by the solid tumour, a bio reductive, tumour targeted drug delivery system was planned.

The system would experience bio reductive activation as well as neighbouring group participation due to arrangement restriction to facilitate drug delivery at the solid tumour site. The constituents of the delivery system significantly modified the rate and extent of anticancer drug delivery.

Bioreversible derivatization of acivicin to a tumor-targeted drug delivery system rendered the anticancer agent unrecognizable to the large neutral amino acid transporter, thus avoiding accumulation in the brain.

On the other hand, antineoplastic agents that resemble large neutral amino acids would facilitate their entry for the treatment of tumor in the brain.

For example, L-meta-sarcolysin was found to be taken up into the brain 100 times more rapidly than melphalan, a para-substituted nitrogen mustard derivative of L-phenylalanine.

Metastasis can be treated by the use of the tumor cells as the drug carrier. Doxorubicin-loaded B16-F10 murine melanoma cells were intravenously administered into C557B1 mice preinoculated with live B16-F10 tumor cells.

Dosing of anticancer agent can be limited by its potential systemic toxicity.7 Intratumoral injections of paclitaxel–ReGel complex have been demonstrated to inhibit tumor growth with no observable systemic toxicity.

The distribution of paclitaxel (PAC) in female athymic nude mice bearing human breast carcinoma xenografts (MDA-231) after an intratumoral injection of a nontoxic, biodegradable thermal gel (ReGel) complexed with 14C-PAC was followed.

Tumor paclitaxel levels decreased slowly over a 6-week period with a half-life of 20 days.

Less than 0.1% of the total radioactivity was distributed to other organs as the drug cleared the tumor environment. Feces (68%) were the major route of elimination with only a small fraction excreted in urine (3%) on day 42.

These results supported the observation of a lack of systemic toxicity through direct intratumoral injection of an anticancer agent in a ReGel complex.

Aptamers are oligonucleotides that possess high affinity for protein targets (0.01–10 nM).8 Tenascin-C is an overexpressed extracellular matrix protein in carcinomas (breast, lung, prostate, and colon), melanoma, and glioblastoma.

An aptamers against tenascin-C, TTA1, prepared by solid-state synthesis with technetium chelator linked to the 5 end of the oligonucleotide, was found to bind with high affinity (5 nM) and specificity to the target protein.

Blood clearance of the aptamer was rapid with t1/2 < 2 min, following intravenous administration of 3.25 mg/kg of 99mTc-labeled aptamer in athymic mice with human U251 glioblastoma xenografts.

At 1 h, tumor uptake was 3.6% injected dose (ID)/g of tumor, whereas a nonbinding control aptamer displayed low tumor uptake, 0.15% ID/g of tumor.

TTA1’s tumor/blood ratio was 25 at 1 h, 100 at 9.5 h, and 200 at 17 h. Aptamers may be an important entity in the treatment of patients with cancer.

VI. BIODEGRADABLE DRUG DELIVERY SYSTEM

One of the ideal situations in the treatment of disease is the delivery of efficacious medication to the site of action in a controlled and continual manner at the appropriate concentration.

Controlled-released, biodegradable nanoparticles that can be loaded with the appropriate drug products have been developed to treat conditions such as cancer, arthritis, and osteoporosis.

In view of their low toxicity and their protein-binding properties, the nanoparticles may be useful in the oral administration of peptides, proteins, and oligonucleotides, especially for vaccination.

A. Characteristics of Nanoparticles

The properties of nano particles is based on surface morphology, specific surface area, particle drug incorporation, size distribution, bulk density, capacity, release, hydrophobicity, biodegradability, and bioadhesiveness.

Nanoparticles (microspheres) loaded with the drug product can be formulated using copolymers, e.g., poly(lactide-co-glycolide) (PLG) or poly(lactide-co-ethylphosphate), by solvent extraction/evaporation technique.

During the preparation of nanoparticles, process variables, such as phase volume, polyvinyl alcohol (PVA) concentration, polymer composition, and stir speed, can affect the particle size distribution and in vitro release profiles of the drug, e.g., progesterone for the treatment or prevention of osteoporosis in postmenopausal women.

Decreasing the phase volume from 22–9% increased the rate of progesterone release from the microspheres.

Increasing the PVA concentration increased the percentage of smaller-size microspheres as well as the rate of progesterone release from microspheres of the same sieve-size Fraction.

Polymer composition and stir speed during preparation had a significant effect on the particle size distribution and the release rate of progesterone from the microspheres.

None of these parameters affected the efficiency of encapsulation of progesterone.

The release rate of drug product from the nanoparticles can be engineered through the use of different proportions of reaction reagents.

For example, poly(lactide-co-ethylphosphate) was synthesized by melt polycondensation with lactide, ethyl dichlorophosphate, and propylene glycol.

Non aggregated nanoparticles with an encapsulation efficiency of greater than 96% could be successfully prepared by the solvent evaporation method.

The release rate of the drug product was faster for microspheres with a 5:1 lactide to propylene glycol ratio, followed by polymer microspheres with 8:1 and 10:1 ratios.

Manipulation of the release rate means that the nanoparticles can be used to deliver drug products for various periods of time.

In vitro studies established that the efficacy of most drug products depends both on concentration and exposure time.

Biodegradable nanoparticles consisting of negatively charged sulfobutylPVA-graft-PLG (SB-PVA) were compared with commercial latex beads, PLG, and grafted DEAE-PVA-PLG nanoparticles on the ability to adhere to Caco-2 monolayers grown on permeable filter inserts.

Five times more commercial polystyrene nanoparticles of 50 and 100 nm were shown to attach to the Caco-2 cells than those of 200 and 500 nm.

Two times more SB-PVA nanoparticles of 100-nm adhered to the cultured cells than the commercial polystyrene, PLG, and grafted DEAE-PVA-PLG nanoparticles of the same size. Adhesion of the SB-PVA nanoparticles was further increased by the presence of fluorescein isothiocyanate-conjugated bovine serum albumin.

Fluorescent imaging showed that the 100-nm nanoparticles could be observed intracellularly mostly in the basal cell compartments and were also found within membrane pores below the cell monolayer.

The viability of the Caco-2 cells was not affected up to a nanoparticle concentration of 2.5 mg/mL. Controlled-release biodegradable PLG polymers loaded with parathyroid hormone were formulated as a freeze-dried form with particle size ranging from 27 to 47μ.

The freeze-dried method did not alter the surface morphology, particle size, and parathyroid hormone content or release rate of the microspheres.

The freeze-dried microspheres resuspended very rapidly and uniformly in solution.

In vitro release studies indicated that except for a slight early burst ranging from 4–18%, release of parathyroid hormone from the nanoparticles was very slow over the first 14 days. At 15 days, release of parathyroid hormone accelerated rapidly.

B. In Vivo Applications

Solid tumours took up a four to five fold greater number of particles with an average size of 100 nm (nanometer) than of those with an average size of 200 nm.

The naproxen sodium nanoparticles were more efficacious than the free drug.

Restenosis can be described as reobstruction of blood vessels after a mechanical reopening procedure and is a major complication following coronary artery angioplasty.

VII. PROTEIN DRUG DELIVERY SYSTEM

As stated before, hormones, proteins, and small peptides are not suitable for oral administration without complex modifications in the formulation.

To illustrate the tremendous efforts spent in the delivery of these entities, insulin has been chosen as a model drug for experimentation.

Insulin is the principal drug used to prevent ketosis and sustain life in the treatment of patients with type I (insulin-dependent) diabetes mellitus.

Delivery of proteins such as insulin is a challenge because of the molecular size and the sensitivity of the molecule to the loss of its biological activity through minor alterations in the three-dimensional structure.

The normal mode of delivery of insulin to patients at the present time is through intramuscular, subcutaneous, or intravenous injections.

These delivery methods are not ideal because of

(1) the need for training of the patient or the caretaker in the basic steps of injection,

(2) the fear of needles by patients, and

(3) the feeling of pain and possible fibrotic formation at the injection site. These inconveniences could lead to noncompliance.

A variety of approaches for insulin delivery have been attempted to improve on the bioavailability of this important protein drug.

Advances have been realized in the delivery of insulin through the oral, nasal, rectal, dermatological, and ocular routes.

A. Oral Route

One major roadblock in the delivery of insulin via the oral cavity is the need for the drug to pass through the acidic environment of the stomach and the presence of peptidases in the stomach and the small intestines, resulting in the inactivation of the drug.

Various processes have been generated to improve on the oral bioavailability of the protein.

Insulin can be encapsulated in timereleased dosage forms or micellar formulations, attached to bile acids, modified with amphiphilic polymers, or coadministered with delivery agents.

Time-released dosage forms of insulin were prepared using the compression-coated tablet technique with the core tablets containing insulin and the outer layer composed of polyethylene oxide and polyethylene glycol.

9 During passage through the upper gastrointestinal tract, the outer layer gelated rapidly and allowed water penetration into the core of the tablet for the dissolution of insulin.

At the same time, the outer layer was being gradually eroded until the release of insulin was possible. If the dosage form was engineered correctly, the release of insulin should occur when the formulation reached the small intestines.

One time-released dosage form (TR2) was found to release insulin with a lag time of 2 h in an in vitro dissolution test.

A decrease of plasma glucose level was observed 2 h after oral administration of the insulin dosage form in dogs.

An oral mixed micellar formulation containing 50 units of insulin was administered to normal human subjects, resulting in a serum C-peptide lowering effect similar to that of subcutaneous injection of insulin (10 U) over a 31 2 -hour period postdose.

The onset of action of the oral formulation was faster than that of insulin delivered by the subcutaneous route.

The oral insulin formulation and subcutaneous insulin injection produced a similar blood glucose-lowering effect in 10 type I diabetic patients.

The oral insulin formulation with 30 and 50 U of insulin provided areas under the curve (AUCs) of 77 and 82μU/mL, respectively, representing 55 and 66% of the AUC obtained from injected insulin.

Human insulin was acidified and added to appropriate amounts of sodium palmitate solution containing deoxycholate salt.

Oral administration of these insulin-containing deoxycholate–palmitic acid dispersions at doses from 10 to 40 U/kg to rats and rabbits resulted in a significant reduction of blood glucose level in 30 min.

The glucose-lowering effect lasted for 4 h. Insulin was modified with amphiphilic polymers comprising polyethylene glycol (PEGn with n = 1, 2,…, 50) and an alkyl, fatty residue, or derivatized sugar, resulting in the yield of mono-, di-, and triconjugates.

10 Conjugates that have C6 to C18 chains and conjugates with a derivatized sugar moiety were highly resistant to degradation by chymotrypsin in vitro.

Monoconjugates with small PEG units (n = 3–7) were demonstrated to have potency in the depression of blood glucose levels comparable to that of nonconjugated insulin when both were delivered subcutaneously in mice.

B. Pulmonary Route

Delivery of medication through the nasal route has been recognized as a viable alternative to traditional oral administration.

Formulations containing nanoparticulate heparin complexed to insulin were prepared by mixing aqueous solutions of insulin and low molecular weight heparinic acid (insulin– heparin at 20:80 w/w).

The formulation (0.1 mL) was administered to the lungs of anesthetized male New Zealand White rabbits through a catheter.

The insulin–heparin complex (1 U/kg dose of insulin) produced a prolonged decrease in the blood glucose levels for 5 h following nasal administration.

The blood glucose levels were lowered by 88 and 70% within 2 h and at the end of 5 h, respectively.

Comparatively, the hypoglycemic effect of the insulin– heparin complex was three times that of neutral protamine Hegedorn insulin. It was proposed that heparin enhances the absorption of insulin in the lung.

C. Rectal Route

Insulin can be delivered through the rectal route.

Comparatively, it took a longer time for insulin-containing solid suppository to lower the plasma glucose levels of these animals.

The optimal gelation temperature, gel strength, and bioadhesive force of this preparation were 32 ◦C, 22.3 s, and 3800 dynes/cm2, respectively.

No morphological damage to the rectal tissues was noticed following the insertion of the liquid suppository.

D. Dermatological Route

Compressed helium gas was used in a dermal Powder Ject device to deposit insulin in dry powder preparation into the skin for subsequent absorption into the systemic circulation.

11 Powdered formulations containing human insulin were prepared by freeze-drying, compression, milling, and then sieving (38– 53μm) using a sodium phosphate mixture as the bulking excipient.

One milligram of the insulin formulation was administered via the dermal Powder Ject device to shaved skins of anesthetized Sprague-Dawley rats at doses equivalent to 0, 1, 3, and 10 U/kg insulin.

Pharmacokinetic analysis showed that the AUC of insulin correlated with the doses. In the first 60 min following administration, the blood glucose levels of these rats were lowered significantly.

The action of insulin was observed for longer than 240 min following the 3 and 10 U/kg doses. Insulin treatment (10–50 mg/g formulation) was administered by a trans-dermal patch adhered to the abdomen of anaesthetised Sprague–Dawley rats made diabetic by a single injection of streptozotocin (55 mg/kg). Blood was sampled from a tail vein every 2–4 h for 48 h.

E. Ocular Route

Medication can be delivered through the eye in the form of eye drops or in an ocular device. Sodium (Na) or zinc (Zn) insulin was integrated into a Gel foam sponge supported device.

An in vitro dissolution test indicated that the release of insulin from the device was proportional to the flow rate of the dissolution medium.

An in vivo dissolution experiment provided support for the hypothesis that there was a direct relationship between the prolonged pharmacological response to insulin and its release from the device.

The ocular device with or without the aid of an enhancer was placed in the eye of rabbits as an ocular insert and produced a uniform blood glucose-lowering effect of 60% over 8 h.

The blood glucose level gradually returned to the baseline level if the device was removed from the eye.

It was feasible that the slow and continuous rate of tear production and its elimination through the lower cul-de-sac assisted the prolonged release of insulin and its continual pharmacological action.

Comparatively, only a blood glucose-lowering spike was observed over 1.5 h following the delivery of the same dose of insulin and an enhancer by an eyedrop.

VIII. DEVICES

A. Needle

Enteral route: It uses the natural form of absorption that is the intestine, although these substances are not only ingested through the mouth, but are deposited directly in other sections of the intestine such as the rectum.

The substance is supplied in food, in drinking water, or by forced administration using a probe.

Parenteral route: This pathway involves the breakdown of the body’s barriers, the skin and the mucous membranes to deposit the substances in tissues or internal cavities of the body, such as the abdominal one.

The most common method is the injection with deposits of substances inside the skin (intradermal ID), or under it in the subcutaneous tissue (subcutaneous SC) in the muscles (intramuscular IM), in veins (intravenous IV), or in cavities such as the pleura (intra pleural route) or peritoneal (intraperitoneal IP route).

INJECTIONS REMEMBER NEVER FORGET:

Use antiseptics in each of the substance administration procedures.

USE THE MOST SUITABLE NEEDLES: Inserting large needles can be painful and results in excessive tissue damage. Those of small caliber make it difficult for the inoculum to pass.

LOOK AT THE CALIBER: The gauge of the needle depends on the resistance of the tissues it has to penetrate, which in turn depends on the animal species and the injection site.

DO NOT RECYCLE THE MATERIAL: Change the needle with each animal. The needles become blunt and the puncture becomes more painful.

LOOK FOR ALTERNATIVES: If the procedure must be repeated frequently, consider catheterizing the vein for example.

ENTER THE SELECTED ROUTE: Entering an unwanted road can have serious consequences, even fatal. ASPIRE: Retract the plunger before administering the substance.

ACHIEVE PRECISION: You can achieve greater precision on insertion depth by using stops or markings on the needles and probes.

SOFTLY: Insert the needle / probe firmly but gently and push the plunger gently. After the injection, slowly but firmly pull the needle out.

IMPORTANT: Fluids can leak through the inoculation point reducing dose accuracy. Shift the skin; You can massage the puncture site to disperse the substrate.

B. Implants

The birth control implant (also known as Nexplanon) is a small, thin rod about the size of a matchstick.

The implant releases hormones in the body that prevent pregnancy. A nurse or doctor places the implant in your arm, and voila: you have protection against pregnancy for a period of up to 5 years.

It is the contraceptive method to “put on and forget” The birth control implant is a small, thin rod about the size of a matchstick.

It is also known as Nexplanon, and there is a slightly older version called Implanon.

A doctor places the implant under the skin of your arm and it releases the hormone progestin to prevent you from getting pregnant.

C. Inhalers

Inhalers

An aerosol is a suspension or a solution (in the case of the Modulite System) of small liquid or solid particles in a gas.

Nebulizers are used to generate liquid particles, while INHALERS are used to generate solid particle aerosols, which can be: in dry powder called IPS or DPI (Dry Power Inhalers). in pressurized cartridge called ICP or MDI (Metered Dose Inhalers).

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